Compounds, which are potent inhibitors of Na+ /Ca2+ exchange mechanism and are useful in the treatment of arrhythmias

ABSTRACT

Therapeutically active compounds of formula (I): 
                         
wherein the variables shown in formula (I) are defined in the disclosure; and pharmaceutically acceptable salts and esters thereof. The compounds are potent inhibitors of the Na + /Ca 2+  exchange mechanism.

This application is a U.S. national stage filing of PCT Internationalapplication Ser. No. PCT/FI02/00621, filed on Jul. 10, 2002, whichclaims the benefit of priority to Finnish patent application no.20011507, filed on Jul. 10, 2001.

TECHNICAL FIELD

The present invention relates to new therapeutically active compoundsand pharmaceutically acceptable salts and esters thereof. The inventionalso relates to pharmaceutical compositions containing these compoundsas active ingredients. The compounds of the invention are potentinhibitors of Na⁺/Ca²⁺ exchange mechanism.

BACKGROUND OF THE INVENTION

Na⁺/Ca²⁺ exchange mechanism is one of the ion transport mechanisms thatregulate the concentration of sodium and calcium ions in the cells.Compounds which selectively inhibit Na⁺/Ca²⁺ exchange mechanism andthereby prevent overload of Ca²⁺ in cells are regarded useful inpreventing the cell injury mechanism of cardiac muscle and the likeafter ischemia and reperfusion. Such compounds are useful in thetreatment of ischemic heart diseases, ischemic cerebral diseases,ischemic renal diseases and in the protection of cells duringthrombolytic therapy, angioplasty, bypass operation of coronary arteryor organ transplantation and arrhythmias.

Compounds capable of inhibiting Na⁺/Ca²⁺ exchange system have beendescribed earlier e.g. in patent publications WO 97/09306, EP 0978506,EP 1031556, JP 11049752 and JP 11302235.

SUMMARY OF THE INVENTION

It has now been found that compounds of formula (I) are particularlypotent inhibitors of Na⁺/Ca²⁺ exchange mechanism and are particularlyuseful in the treatment of arrhythmias.

The compounds of the present invention have a structure represented byformula (I):

wherein

X is —O—, —CH₂— or —C(O)—;

Z is —CHR₉— or valence bond;

Y is —CH₂—, —C(O)—, CH(OR₁₀)—, —CH(NR₁₁R₁₂)—, —O—, —S—, —S(O)— or—S(O₂)—

provided that in case Z is a valence bond, Y is not C(O);

the dashed line represents an optional double bond in which case Z is—CR₉— and Y is —CH—, C(OR₁₀)— or —C(NR₁₁R₁₂)—;

R₁ is —(CH₂)_(n)NR₄R₇ or one of the following groups:

n is 1-4,

R₂ and R₃ are independently H, lower alkyl, lower alkoxy, —NO₂, halogen,—CF₃, —OH, —NHR₈ or —COOH,

R₄ and R₇ are independently H, lower alkyl or lower hydroxyalkyl,

R₅ is H, lower alkoxy, —CF₃, —NH₂ or —CN,

R₆ is —NO₂, —NR₁₄R₁₉, —CF₃ or

R₈ and R₁₆ are independently H or acyl,

R₉ is H or lower alkyl,

R₁₀ is H, alkylsulfonyl or acyl;

R₁₁ and R₁₂ are independently H, lower alkyl or acyl,

R₁₃ and R₁₈ are independently H or —OR₂₀,

R₁₄ and R₁₉ are independently H, acyl, alkylsulfonyl, C(S)NHR₁₇ orC(O)NHR₁₇,

R₁₅ is H or NH₂,

R₁₇ is H or lower alkyl,

R₂₀ is H or acyl,

and pharmaceutically acceptable salts and esters thereof.

In one class of preferred compounds and pharmaceutically acceptablesalts and esters thereof are compounds of formula

wherein R₁, R₂, R₃, X, Y and Z are as defined above. In another class ofpreferred compounds and pharmaceutically acceptable salts and estersthereof are compounds of formula (I), wherein X is O, and Z and Y is—CH₂—. In another class of preferred compounds and pharmaceuticallyacceptable salts and esters thereof are compounds of formula (I),wherein X is O, and Z is —CH₂— and Y is CHOH.

In one subclass of preferred compounds and pharmaceutically acceptablesalts and esters thereof are compounds of formula (I) wherein R₁ is oneof the following groups

In another subclass of preferred compounds are compounds, wherein R₆ is—NO₂ or—NR₁₄R₁₉. In a group of this subclass R14 and R19 areindependently H, acyl or alkylsulfonyl, R₁₅ and R₁₆ is preferably H andR₅ is H or lower alkoxy.

In one subclass of preferred compounds are compounds, wherein R₂ and R₃are independently H or halogen. Fluorine is the preferred halogen.

In one class of preferred compounds are compounds wherein n=2. R₄ and R₇are preferably methyl.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) together with a pharmaceuticallyacceptable carrier.

The present invention further provides a method for inhibiting Na⁺/Ca²⁺exchange mechanism in a cell, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound of formula(I).

The present invention further provides a method for preventing overloadof Ca²⁺ ions in cells, comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method for treatingarrhythmias, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the antiarrhythmic effects of the compound of Example 27 onouabain-induced aftercontractions in guinea-pig isolated papillarymuscles.

FIG. 2 shows the antiarrhythmic effects of the compound of Example 67 onouabain-induced aftercontractions in guinea-pig isolated papillarymuscles.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention can be prepared from corresponding phenolderivatives (II), wherein R₂, R₃, X, Z and Y are the same as definedabove.

The syntheses are shown in Scheme 1, wherein formula (II) is abbreviatedas Ar—OH (II), and R₄, R₅, R₆, R₇, R₁₅ and R₁₆ are the same as definedabove, and Hal means halogen.

Compounds of formula (II) can be reacted with 1-chloro-2-nitrobenzenederivatives to result in nitrophenoxy compounds (10), which in turn byhydrogenation gives phenylamine derivatives (11). 5-Nitropyridin-2-yloxyderivatives (12) are obtained by reactions with2-chloro-5-nitropyridine.

2-Oxymethyl imidazoline derivatives (14) can be synthesised from phenolderivatives (II) via cyano methyl ether (13), which is converted toimidazoline (14) by a known method (e.g. J. Med. Chem. 1994, 37(12),1874). Alkoxyazide derivatives (16) are obtained via correspondinghaloalkoxy derivatives (15) by reaction with sodium azide. Azides (16)are converted to amines (17) by reaction with triphenylamine.2-(Dimethylamino)ethoxy derivatives (18) are obtained by directreactions of phenols of formula (II) with 2-(dimethylamino)ethylchloride.

The reduction of nitropyridines (22) followed by acylation, mesylationetc. produces compounds of formula (24), as shown by Scheme 2.

As shown in the following Scheme 3, wherein R₂ and R₃ are the same asdefined above, 6- and 7-hydroxyflavane derivatives (2) are obtained fromcorresponding flavanones (1) by Clemmensen reduction. 6- and7-hydroxyflavanones (1) are commercially available or can be synthesisedby methods described in the literature, e.g. J. Org Chem., 1960, 25,1247-9 and J. Org. Chem., 1958, 23, 1159-61 or as described later inScheme 5.

The following Scheme 4, wherein R₂ and R₃ are the same as defined above,describes the synthesis of 2-phenyl indan-5-ols (9). Condensation ofp-anisaldehyde (3) with substituted phenyl acetic acid (4) gives mixtureof cis- and trans-isomers of the corresponding acrylic acid (5). Afterhydrogenation and intramolecular Friedel-Crafts reaction carbonylfunctionality of 1-indanones (7) can be reduced by Clemmensen reduction.Finally methoxy indane (8) is refluxed in concentrated hydrobromic acidto obtain 2-phenyl indan-5-ols (9).

6-Hydroxyflavanone derivatives can be synthesised as shown in Scheme 5.2′,5′-Dihydroxyacetophenone or corresponding propiophenone is condensedwith appropriate benzaldehyde resulting in a mixture of desired6-hydroxyflavanone (36) and the corresponding chalcone (35). Thechalcone can be cyclised to flavanone.

2-Phenylchroman-4,6-diol derivatives (37) are obtained fromcorresponding 6-hydroxyflavanones (36) by reduction as shown in Scheme6. These diol derivatives can be reduced further into 6-hydroxyflavanes(38).

As shown in the following Scheme 7, the 4-amino-2-phenylchromanolderivatives (19) can be synthesised from corresponding flavanones (1)via hydroxy-2-phenylchroman-4-one oximes (20). Reduction of oximederivative gives 4-amino-2-phenylchromanols (21) which can be alkylatedor acylated by common methods. 4-Hydroxy-2-phenylchromanol derivativescan be treated by similar methods.

The following Scheme 8, wherein R₂ and R₃ are the same as defined above,describes the synthesis of 7-hydroxyisoflavones (29) and7-hydroxyisoflavans (30). Acylation of 3-methoxyphenol with substitutedphenyl acetic acids gives the corresponding 2-hydroxydeoxybenzoins (27)which can be cyclised with triethylortoformate to yield isoflavones(28). Deprotection with hydrobromic acid and catalytic hydrogenationgives 7-hydroxyisoflavans (30).

The following Scheme 9 describes the synthesis of2-phenyl-2,3-dihydro-enzo[1,4]oxathiin-6-ol (34). The reaction of2-mercaptobenzene-1,4-diol with styrene epoxide in the presence of basegives sulfide (33). The ring closure with an acid ion exchanger affords2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol (34).

The following Scheme 10 describes the synthesis of6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (41) and6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (40). Pd-catalyzedα-arylation of 6-methoxy-1-tetralone gives6-methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (39) which afterdemethylation leads to the phenolic compound (40).

The following Scheme (11), wherein R₂ and R₃ are the same as definedabove, describes the synthesis of2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ols (45). After protectinghydroxyl groups of 2,5-dihydroxyacetophenone this ketone rearranges withperacids and gives a phenol after hydrolysis. The phenol is condensedwith a haloketone and after reduction and removal of protection groupsthe hydroxyphenol (44) is cyclised to a2,3-dihydro-2-phenyl-benzo[1,4]-dioxin-6-ol (45).

Salts and esters of the compounds, when applicable, may be prepared byknown methods. Physiologically acceptable salts are useful as activemedicaments. Examples are the salts with inorganic acids such ashydrochloric acid, hydrobromic acid or nitric acid, and salts withorganic acids such as methanesulfonic acid, citric acid or tartaricacid. Physiologically acceptable esters are also useful as activemedicaments. Examples are the esters with aliphatic or aromatic acidssuch as acetic acid or with aliphatic or aromatic alcohols.

The term “alkyl” as employed herein by itself or as part of anothergroup includes both straight, branched and cyclized chain radicals of upto 18 carbon atoms, preferably 1 to 7 carbon atoms, most preferably 1 to4 carbon atoms. The term “lower alkyl” as employed herein by itself oras part of another group includes straight, branched and cyclized chainradicals of 1 to 7, preferably 1 to 4, most preferably 1 or 2 carbonatoms. Specific examples for the alkyl and lower alkyl residues,respectively, are methyl, ethyl, propyl, isopropyl, butyl, tert. butyl,pentyl, cyclopentyl, hexyl, cyclohexyl, octyl, decyl and dodecylincluding the various branched chain isomers thereof.

The term “alkoxy” as employed herein by itself or as part of anothergroup includes an alkyl group as defined above linked to an oxygen atom.

The term “acyl” as employed herein by itself or as part of another grouprefers to an alkylcarbonyl or alkenylcarbonyl group, the alkyl andalkenyl groups being defined above.

Compounds of the invention may be administered to a patient intherapeutically effective amounts which range usually from about 0.05 to200 mg, preferably 0.1 to 100 mg, more preferably 0.5 to 50, mg per daydepending on the age, weight, condition of the patient, administrationroute and the Na⁺/Ca²⁺ exchange inhibitor used. The compounds of theinvention can be formulated into dosage forms using the principles knownin the art. It can be given to a patient as such or in combination withsuitable pharmaceutical excipients in the form of tablets, granules,capsules, suppositories, emulsions, suspensions or solutions. Choosingsuitable ingredients for the composition is a routine for those ofordinary skill in the art. It is evident that suitable carriers,solvents, gel forming ingredients, dispersion forming ingredients,antioxidants, colours, sweeteners, wetting compounds and otheringredients normally used in this field of technology may be also used.The compositions containing the active compound can be given enterallyor parenterally, the oral route being the preferred way. The contents ofthe active compound in the composition is from about 0.5 to 100%,preferably from about 0.5 to about 20%, per weight of the totalcomposition.

Experiments

The effects of the compounds of the invention were tested onouabain-induced arrhythmias in guinea-pig papillary muscles.

Methods

Guinea-pig papillary muscles were mounted into horizontal musclecuvette. A hook connected to force transducer was attached to anotherend of the muscle. Muscle preparations were electrically paced at 1 Hzwith field stimulation via platinum electrodes. Modified Tyrode solutionwas used for superfusion of muscle preparations. The composition of theTyrode solution was the following (mM): NaCl 135, MgCl₂×6H₂O 1, KCl 5,CaCl₂×2H₂O 2, NaHCO₃ 15, Na₂HPO₄×2H₂O 1, and glucose 10. The Tyrodesolution was gassed with carbogen (95% O₂, 5% CO₂) to set pH at 7.4.Experiments were carried out at 37° C. Acquisition and analysis oftwitch tensions with Action Potential and Force Measurement System (ACFOv1.0, Fision Ltd, Finland).

Inhibition of Ouabain-Induced Arrhythmias

Ouabain by blocking of sodium-potassium ATPase increase intracellularsodium which is changed for calcium via NCX. Increased intracellularcalcium is leading to overload of sarcoplasmic reticulum (SR) andspontaneous calcium release from SR inducing delayed afterpolarizations(DADs). Equivalence for DADs in force signal is aftercontractions (ACs)which are seen as spontaneous twitches after the pacing controlledtwitch.

The compounds of the invention delayed appearance and decreasedamplitude of aftercontractions. As shown in FIG. 1, the title compoundof Example 27, at 30 μM concentration, delayed appearance [38±7.5 min vsvehicle: 25±8.9 min (mean±SD), p=0.013, n=5] and decreased maximumamplitude of aftercontractions #1 (74±16 mg vs vehicle: 143±54 mg,p=0.008, One-way ANOVA followed by LSD; n=5). As shown in FIG. 2, thetitle compound of Example 67, at 10 μM, decreased maximum amplitude ofaftercontractions #1 (88±20 mg vs vehicle: 143±54 mg, p=0.027, n=5).

EXAMPLES Example 1 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine a)2-phenylchroman-6-ol

Zinc (5.4 g, 83.2 mmol), mercury (II) chloride (340 mg), concentratedhydrogen chloride (0.2 ml) and water were mixed at room temperature for15 minutes and the mixture was decanted. 6-Hydroxyflavanone (1.0 g) wasadded as a suspension in a mixture of acetic acid (25 ml), concentratedhydrogen chloride (5.2 ml) and water (2 ml). The reaction mixture wasrefluxed for 1½ hours. After cooling into room temperature, the reactionmixture was filtered and the filtrate was extracted with ethyl acetate.The combined organic layers were washed with saturated NaHCO₃-solution,then with water and dried with Na₂SO₄. The 2-phenylchroman-6-ol waspurified by column chromatography using heptane-ethyl acetate (2:1) asan eluant. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.78 (s, 1H), 7.43-7.31 (m, 5H),6.63 (d, 1H, J 8.6 Hz), 6.51 (dd, 1H, J 8.6, 2.9 Hz), 6.48 (d, 1H, J 2.9Hz), 4.98 (dd, 1H, J, 9.9, 2.2 Hz), 2.89 (ddd, 1H, J −16.7, 11.3, 6.1Hz), 2.63 (ddd, 1H, J −16.7, 5.5, 3.3 Hz) 2.10 (m, 1H), 1.94 (m, 1H).

b) 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine

Potassium fluoride (225 mg) was added into a solution of2-phenylchroman-6-ol (300 mg) in dry DMF (3 ml). After stirring theresulting mixture at 120° C. for 30 minutes 2-chloro-5-nitropyridine(195 mg) was added. The reaction mixture was stirred for a further 6½hours at 120° C. After cooling into room temperature 1 M HCl-solutionwas added and the mixture was extracted with ethyl acetate. The combinedorganic layers were washed with water then with saturated NaCl-solutionand dried with Na₂SO₄. 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine wasrecrystallised from acetone-2-propanol (1:5). ¹H NMR (400 MHz, d₆-DMSO)δ: 9.00 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.47-7.32 (m,5H), 7.20 (d, 1H, J 9.2 Hz), 7.00-6.89 (m, 3H), 5.15 (dd, 1H, J 10.1,2.2 Hz), 2.99 (ddd, 1H, J −16.8, 11.3, 6.2 Hz), 2.75 (ddd, 1H, J −16.8,5.4, 3.3 Hz), 2.18 (m, 1H), 2.02 (m, 1H).

Example 2 Dimethyl[2-(2-phenylchroman-6-yloxy)ethyl]amine

Cesium carbonate (230 mg) and an excess of 2-(dimethylamino)ethylchloride in ethyl acetate were added into a solution of2-phenylchroman-6-ol (150 mg) in acetonitrile (5 ml). The reactionmixture was refluxed for 30 minutes. After removing the solvents, theresidue was taken up in water and extracted with ethyl acetate. Thecombined organic layers were washed with water and then with saturatedNaCl-solution and dried with Na₂SO₄. Thedimethyl[2-(2-phenylchroman-6-yloxy)-ethyl]amine was crystallised fromheptane. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.43-7.30 (m, 5H), 6.75-6.67 (m,3H), 5.03 (dd, 1H, J 10.0, 2.2 Hz), 3.95 (t, 2H, J 5.9 Hz), 2.94 (ddd,1H, J −16.7, 10.9, 5.8 Hz), 2.69 (ddd, 1H, J −16.7, 5.2, 3.3 Hz), 2.58(t, 2H, J 5.9 Hz), 2.13 (m, 1H), 1.96 (m, 1H).

Example 3 5-Methoxy-2-(2-phenylchroman-6-yloxy) phenylamineHydrochloride a) 6-(4-Methoxy-2-nitrophenoxy)-2-phenylchroman

The 2-phenylchroman-6-ol (500 mg) and 1-chloro-4-methoxy-2-nitrobenzene(390 mg) were dissolved in DMSO (10 ml). Potassium hydroxide (230 mg)and potassium iodide (520 mg) were added and the resulting mixture wasstirred at 90° C. for 1 hour. After cooling it was poured in to 1 MHCl-solution (20 ml) and extracted with dichloromethane. The combinedorganic layers were washed with water until neutral and then withsaturated NaCl-solution and dried with Na₂SO₄. After evaporating thesolvents the 6-(4-Methoxy-2-nitrophenoxy)-2-phenylchroman was obtainedby trituration with methanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.58 (d, 1H,J 3.1 Hz), 7.45-7.33 (m, 6H), 7.28 (dd, 1H, J 9.2 Hz, 3.1 Hz), 7.10 (d,1H, J 9.2 Hz), 6.86-6.78 (m, 3H), 5.10 (dd, 1H, J 10.0, 1.9 Hz), 3.83(s, 3H), 2.92 (ddd, 1H, J −16.9, 11.2, 5.9 Hz), 2.75 (ddd, 1H, J −16.9,7.9, 4.2 Hz), 2.15 (m, 1H), 1.97 (m, 1H).

b) 5-Methoxy-2-(2-phenylchroman-6-yloxy)phenylamine Hydrochloride

6-(4-Methoxy-2-nitrophenoxy)-2-phenylchroman (360 mg) was dissolvedethyl acetate and 10% palladium on carbon (90 mg) was added. Thereaction mixture was hydrogenated for 2 hours at normal pressure androom temperature. It was then filtered through Celite and washed withethyl acetate. The 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine wasisolated as its hydrochloride salt. ¹H NMR (400 MHz, d₆-DMSO) δ:7.44-7.33 (m, 5H), 6.83-6.72 (m, 4H), 6.68 (d, 1H, J 2.9 Hz), 6.48 (dd,1H, J 8.9, 2.8 Hz), 5.07 (dd, 1H, J 10.0, 2.2 Hz), 3.70 (s, 3H), 2.93(ddd, 1H, J −17.0, 11.1, 6.1 Hz), 2.68 (ddd, 1H, J −17.0, 8.3, 4.5 Hz),2.15 (m, 1H), 1.97 (m, 1H).

Example 4 2-(2-Phenylchroman-6-yloxy)ethylamine Methane Sulfonate a)6-(2-azidoethoxy)-2-phenylchroman

2-Phenylchroman-6-ol (340 mg), 1-bromo-2-chloroethane (1.25 ml) andcesium carbonate (977 mg) were dissolved in acetonitrile (4 ml). Thereaction mixture was refluxed for 4 hours. After cooling into roomtemperature it was poured in 1 M HCl-solution and extracted withdichloromethane. The combined dichloromethane extracts were washed withwater and dried with Na₂SO₄. The mixture was passed through silica gelcolumn using ethyl acetate-hexane (1:7) as an eluant resulting 190 mg ofhaloethane derivative. It was dissolved in DMF (5 ml) and sodium azide(214 mg) was added. The reaction mixture was refluxed for 2 hours. Themixture was filtered. Ethyl acetate was added to the filtrate and it wasthen washed once with 1 M HCl-solution and then several times with waterand dried with Na₂SO₄. The solvents were evaporated under reducedpressure to give 6-(2-azidoethoxy)-2-phenylchroman. ¹H NMR (400 MHz,d₆-DMSO) δ: 7.44-7.32 (m, 5H), 6.78-6.71 (m, 3H), 5.04 (dd, 1H, J 10.1,2.3 Hz), 4.10 (t, 2H, J 4.8 Hz), 3.60 (t, 2H, J 4.8 Hz), 2.95 (ddd, 1H,J −16.8, 11.1, 6.0 Hz), 2.70 (ddd, 1H, J −16.8, 5.3, 3.3 Hz), 2.14 (m,1H), 1.97 (m, 1H).

b) 2-(2-Phenylchroman-6-yloxy)ethylamine Methane Sulfonate

Triphenylphosphine (165 mg) and 40 μl of water were added into asolution of 6-(2-azidoethoxy)-2-phenylchroman (155 mg) intetrahydrofuran. The resulting mixture was stirred for 2 hours at roomtemperature. 2-(2-Phenylchroman-6-yloxy)-ethylamine was isolated as itsmethane sulfonate salt. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.91 (bs, 3H),7.44-7.32 (m, 5H), 6.81-6.75 (m, 3H), 5.05 (dd, 1H, J 9.9, 2.3 Hz), 4.08(t, 2H, J 5.1 Hz), 3.19 (m, 2H), 2.95 (ddd, 1H, J −16.8, 11.0, 5.9. Hz),2.71 (ddd, 1H, J −16.8, 5.2, 3.4 Hz), 2.30 (s, 3H), 2.15 (m, 1H), 1.97(m, 1H).

Example 5 2-(2-Phenylchroman-6-yloxymethyl)-4,5-dihydro-1H-imidazoleHydrochloride a) (2-phenylchroman-6-yloxy)acetonitrile

Cesium carbonate (310 mg) and chloroacetonitrile (62 μl) were added intoa solution of 2-phenylchroman-6-ol (200 mg) in acetonitrile (3 ml). Theresulting mixture was refluxed for 6 hours. The reaction mixture wasallowed to cool to room temperature and 1 M HCl-solution was added andit was extracted with ethyl acetate. The combined organic layers werewashed with water and saturated NaCl-solution and dried with Na₂SO₄. Thesolvents were evaporated under reduced pressure to give(2-phenylchroman-6-yloxy)acetonitrile. ¹H NMR (400 MHz, d₆-DMSO) δ:7.44-7.30 (m, 5H), 6.86-6.81 (m, 3H), 5.08 (dd, 1H, J 9.8, 2.2 Hz), 5.07(s, 2H), 2.97 (ddd, 1H, J −16.9, 10.9, 6.0. Hz), 2.71 (ddd, 1H, J −16.9,5.0, 3.4 Hz), 2.15 (m, 1H), 1.97 (m, 1H).

b) 2-(2-Phenylchroman-6-yloxymethyl)4,5-dihydro 1H-imidazoleHydrochloride

Dry HCl was passed through a solution of(2-phenylchroman-6-yloxy)acetonitrile (270 mg) in diethyl ether and 90μl of absolute ethanol while cooling with ice bath. Reaction mixture wasevaporated to the dryness after formation of the intermediate imidate.Precipitate was dissolved in absolute ethanol and 252 μl ethylenediamine was added to the cooled solution. Reaction mixture was allowedto warm to room temperature, evaporated to dryness, dissolved indichloromethane and washed with water. Combined organic layers weredried and treated with charcoal. The2-(2-Phenylchroman-6-yloxymethyl)4,5-dihydro-1H-imidazole was isolatedas its HCl-salt. ¹H-NMR (d₄-MeOH): 7.5-7.2 (m, 5H), 6.85-6.75 (m, 3H),5.01 (d, 1H, J 8.8 Hz), 4.97 (s, 2H), 4.00 (s, 4H), 3.02-2.90 (m, 1H),2.80-2.70 (m, 1H), 2.21-2.12 m, 1H), 2.05-1.90 (m, 1H). (M)⁺=308 (100%)

Example 6 6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one

6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4one was prepared asdescribed for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) using 200 mg of 6-hydroxyflavanone. ¹H NMR (400 MHz, d₆-DMSO) δ:9.03 (bs, 1H), 8.64 (d, 1H, J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 12.3, 2.9 Hz), 3.30 (dd,1H, −16.3, 12.3 Hz), 2.87 (dd, 1H, −16.3, 2.9 Hz).

Example 7 7-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one

7-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared asdescribed for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) using 150 mg of 7-hydroxyflavanone. ¹H NMR (400 MHz, d₆-DMSO) δ:9.07 (d, 1H, J 2.8 Hz), 8.67 (dd, 1H, J 9.0, 2.8 Hz), 7.89 (d, 1H, 8.6Hz), 7.60-7.35 (m, 6H), 7.04 (d, 1H, 2.1 Hz), 6.97 (dd, 1 H, 8.6, 2.1HZ), 5.75 (dd, 1H, J 13.0, 2.7 Hz), 3.32 (dd, 1H, 16.9, 13.0 Hz), 2.85(d, −16.9, 2.7 Hz).

Example 8 6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol a)2-Phenylchroman-4,6-diol

Into a suspension of 6-hydroxyflavanone (1.0 g) in dry THF (11.5 ml) wasadded dropwise a solution of borane-THF complex (12.5 ml, 1.0 M in THF)under nitrogen. The reaction mixture was refluxed for 1 hour. Aftercooling to the room temperature it was poured into an ice-2 MHCl-solution. 2-Phenylchroman-4,6-diol was filtered. ¹H NMR (400 MHz,d₆-DMSO) δ: 8.83 (s, 1H), 7.45-7.38 (m, 4H), 7.35 (m, 1H), 6.89 (d, 1H,J 2.8 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz), 5.41(d, 1H, J 7.0 Hz), 5.11 (dd, 1H, J 11.7, 1.2 Hz), 4.87 (m, 1H), 2.26 (m,1H), 1.90 (m, 1H).

b) 6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol

6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.5 g of 2-phenylchroman-4,6-diol. The product waspassed through a silica gel column using toluene-ethyl acetate (4:1) asan eluant and then crystallised from 2-propanol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.7 Hz), 8.61 (dd, 1H, J 9.1, 2.7 Hz),7.50-7.36 (m, 5H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00(dd, 1H, J 8.7, 2.7 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.65 (d, 1H, J 6.3 Hz),5.30 (dd, 1H, J 11.9, 1.3 Hz), 4.99 (m, 1H), 2.33 (m, 1H), 1.98 (m, 1H).

Example 9 2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(3-Fluorophenyl)-6-hydroxychroman-4-one

2′,5′-Dihydroxyacetophenone (1.50 g) was dissolved in warm glacialacetic acid (26 ml). 3-Fluorobenzaldehyde (1.35 g) and ammonium acetate(0.98 g) were added. The reaction mixture was refluxed for 2 hours. Itwas allowed to cool to room temperature and poured in ice. Theprecipitate formed was filtered resulting in 2.2 g of a mixture of2-(3-fluorophenyl)-6-hydroxychroman-4-one and1-(2,5-dihydroxyphenyl)-3-(3-fluorophenyl)propenone. The obtainedmixture was dissolved in ethanol (90 ml) and sodium acetate (1.75 g) wasadded. The reaction mixture was refluxed for 5 hours. It was thenallowed to cool to room temperature and diluted with water and filtered.The 2-(3-fluorophenyl)-6-hydroxychroman-4-one was recrystallised fromacetic acid. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.45 (s, 1H), 7.47 (m, 1H),7.40-7.37 (m, 2H), 7.22 (m, 1H), 7.12 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J8.8, 3.0 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.59 (dd, 1H, J 13.0, 2.9 Hz),3.21 (dd, 1H, J −16.9, 13.0 Hz), 2.82 (dd, 1H, J −16.9, 2.9 Hz).

b) 2-(3-Fluorophenyl)chroman-4,6-diol

2-(3-Fluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 220 mg of2-(3-fluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.85 (s, 1H), 7.45 (m, 1H), 7.30-7.25 (m, 2H), 7.15 (m, 1H), 6.88 (d,1H, J 2.8 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz),5.44 (d, 1H, J 7.0 Hz), 5.15 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.29 (m,1H), 1.86 (m, 1H).

c) 2-(3-Fluorophenyl)chroman-6-ol

Triethylsilane (960 μl) was added slowly into a solution of2-(3-fluorophenyl)chroman-4,6-diol (195 mg) in dichloromethane (4 ml).Trifluoroacetic acid (1.9 ml) was then added dropwise into a reactionmixture and it was stirred at room temperature for 5 hours. The reactionmixture was poured on ice-water and extracted with dichloromethane. Theresidue was evaporated under reduced pressure with toluene to obtain2-(3-fluorophenyl)chroman-6-ol. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.78 (s,1H), 7.43 (m, 1H), 7.28-7.25 (m, 2H), 7.14 (m, 1H), 6.66 (d, 1H, J 8.5Hz) 6.52 (dd, 1H, J 8.5, 2.7 Hz), 6.49 (d, 1H, J 2.7 Hz), 5.03 (dd, 1H,J 9.9, 2.1 Hz), 2.86 (m, 1H), 2.63 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).

d) 2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 210 mg of 2-(3-fluorophenyl)chroman-6-ol. The productwas recrystallised from 2-propanol. ¹H NMR (400 MHz, CDCl₃) δ: 9.07 (d,1H, J 2.8 Hz), 8.46 (dd, 1H, J 9.0, 2.8 Hz), 7.36 (m, 1H), 7.21-7.15 (m,2H), 7.03 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.98 (d, 1H, J 8.6 Hz), 6.92(dd, 1H, J 8.6, 2.7 Hz), 6.90 (d, 1H, J 2.7 Hz), 5.09 (dd, 1H, J 10.3,2.4 Hz), 3.01 (ddd, 1H, J −16.9, 11.4, 6.0 Hz), 2.82 (ddd, 1H, J −16.9,5.1, 3.2 Hz), 2.24 (m, 1H), 2.09 (m, 1H).

Example 10 5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine a)2-Phenylchroman-7-ol

2-Phenyl-chroman-7-ol was prepared as described for5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(a) startingfrom 1.0 g of 7-hydroxy-flavanone. The product was purified by columnchromatography using heptane-ethyl acetate (2:1) as an eluant. ¹H NMR(400 MHz, CD₃OD) δ: 7.41-7.28 (m, 5H), 6.86 (d, 1H, J 8.2 Hz), 6.32 (dd,1H, J 8.2, 2.4 Hz), 6.29 (d, 1H, J 2.4 Hz), 5.00 (dd, 1H, J 9.9, 2.4Hz), 2.84 (m, 1H), 2.64 (m, 1H), 2.15 (m, 1H), 1.99 (m, 1H).

b) 5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine

5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine was prepared as describedfor 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) startingfrom 115 mg of 2-phenylchroman-7-ol. The product was purified onpreparative TLC-plate covered with silica gel using toluene-ethylacetate (15:1) as an eluant. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, 1H, J9.1 Hz), 7.20 (d, 1H, J 8.9 Hz), 6.72 (dd, 1H, J 8.9, 2.3 Hz), 6.72 (d,1H, J 2.3 Hz), 5.16 (dd, 1H, J 10.1, 2.1 Hz), 2.97 (ddd, 1H, J −16.7,11.3, 5.9 Hz), 2.77 (ddd, 1H, J −16.7, 8.1, 4.5 Hz), 2.20 (m, 1H), 2.02(m, 1H).

Example 11 2-[2-(2,4-Dichlorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(2,4-Dichlorophenyl)-6-hydroxychroman-4-one

2-(2,4-Dichlorophenyl)-6-hydroxychroman-4-one was prepared as describedfor 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) startingfrom 1.0 g of 2′,5′-dihydroxyacetophenone and 1.4 g of2,4-dichlorobenzaldehyde. The product was recrystallised from aceticacid. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.49 (s, 1H), 7.78 (d, 1H, J 8.5 Hz),7.71(d, 1H, J 2.0 Hz), 7.57 (dd, 1H, J 8.5, 2.0 Hz), 7.14 (d, 1H, J 3.0Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H,J 13.5, 2.7 Hz), 3.18 (dd, 1H, J −16.9, 13.5 Hz), 2.78 (dd, 1H, J −16.9,2.7 Hz).

b) 2-(2,4-Dichlorophenyl)chroman-4,6-diol

2-(2,4-Dichlorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1.2 g of2-(2,4-dichlorophenyl)-6-hydroxychroman-4-one. The product was purifiedby column chromatography using heptane-ethyl acetate (2:1) as an eluant.¹H NMR (400 MHz, d₆-DMSO) δ: 8.89 (s, 1H), 7.66 (d, 1H, J 2.1 Hz), 7.64(d, 1H, J 8.5 Hz), 7.51 (dd, 1H, J 2.1, 8.5 Hz), 6.89 (d, 1H, J 2.7 Hz),6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 2.7, 8.7 Hz), 5.50 (d, 1H, J 6.8Hz), 5.37 (d, 1H, J 10.4 Hz), 4.90 (m, 1H), 2.32 (m, 1H), 1.80 (m, 1H).

c) 2-(2,4-Dichlorophenyl)chroman-6-ol

2-(2,4-Dichlorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 625 mg of2-(2,4-dichlorophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ:8.85 (s, 1H), 7.65 (d, 1H, J 2.2 Hz), 7.57 (d, 1H, J 8.4 Hz), 7.49 (dd,1H, J 8.4, 2.2 Hz), 6.67-6.51 (m, 3H), 5.21 (dd, 1H, J 10.3, 2.1 Hz),2.91 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H).

d) 2-[2-(2,4-Dichlorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-5-nitropyridine was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 530 mg of 2-(2,4-dichlorophenyl)chroman-6-ol. Theproduct was purified on preparative TLC-plate covered with silica gelusing heptane-ethyl acetate (3:1) as an eluant. ¹H NMR (400 MHz, CDCl₃)δ: 9.06 (d, 1H, J 2.7 Hz), 8.47 (dd, 1H, J 9.0, 2.7 Hz), 7.56 (d, 1H, J8.4 Hz), 7.41 (d, 1H, J 2.0 Hz), 7.33 (dd, 1H, J 8.4, 2.0 Hz) 7.02 (d,1H, J 9.0 Hz), 6.99-6.92 (m, 3H), 5.39 (dd, 1H, J 10.4, 2.2 Hz), 3.06(ddd, 1H, J −16.9, 11.9, 6.0 Hz), 2.83 (ddd, 1H, J −16.9, 5.3, 2.7 Hz),2.34 (m, 1H), 1.89 (m, 1H).

Example 12 2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(3-Chlorophenyl)-6-hydroxychroman-4-one

2-(3-Chlorophenyl)-6-hydroxychroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from2.0 g of 2′,5′-dihydroxyacetophenone and 1.85 g of 3-chlorobenzaldehyde.The product was recrystallised from acetic acid. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.47 (s, 1H), 7.62 (s, 1H), 7.51-7.45 (m, 3H), 7.12 (d, 1H,J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.58(dd, 1H, J 13.1, 2.9 Hz), 3.18 (dd, 1H, J −16.9, 13.1 Hz), 2.81 (dd, 1H,J −16.9, 2.9 Hz).

b) 2-(3-Chlorophenyl)chroman-4,6-diol

2-(3-Chlorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 730 mg of2-(3-chloro-phenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.85 (s, 1H), 7.50 (d, 1H, J 1.7 Hz), 7.46-7.38 (m, 3H), 6.88 (d, 1H, J2.5 Hz), 6.62 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.5 Hz), 5.44 (d,1H, J 6.6 Hz), 5.15 (dd, 1H, J 11.8, 1.4 Hz), 4.87 (m, 1H), 2.29 (m,1H), 1.85 (m, 1H).

c) 2-(3-Chlorophenyl)chroman-6-ol

2-(3-Chlorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 635 mg of2-(3-chloro-phenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ: 8.79(s, 1H), 7.48 (d, 1H, J 0.7 Hz), 7.42-7.37 (m, 3H), 6.71-6.49 (m, 3H),5.04 (m, 1H), 2.91 (m, 1H), 2.65 (m, 1H), 2.12 (m, 1H), 1.93 (m, 1H).

d) 2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 590 mg of 2-(3-chlorophenyl)chroman-6-ol. The productwas recrystallised from a 3:1 mixture of 2-propanol and ethyl acetate.¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0,2.9 Hz), 7.53 (s, 1H), 7.467-7.42 (m, 3H), 7.20 (d, 1H, J 9.0 Hz), 7.00(dd, 1H, J 8.7, 2.7 Hz), 6.97 (d, 1H, J 2.7 Hz), 6.94 (d, 1H, J 8.7 Hz),5.18 (dd, 1H, J 10.2, 2.2 Hz), 2.97 (ddd, 1H, J −17.0, 11.5, 5.9 Hz),2.83 (ddd, 1H, J −17.0, 8.1, 4.5 Hz), 2.21 (m, 1H), 2.00 (m, 1H).

Example 13 2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(3,5-Difluorophenyl)-6hydroxychroman-4-one

2-(3,5-Difluorophenyl)-6-hydroxychroman-4-one was prepared as describedfor 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) startingfrom 1.0 g of 2′,5′-dihydroxyacetophenone and 1.12 g of3,5-difluorobenzaldehyde. The product was recrystallised from aceticacid. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.47 (s, 1H), 7.30-7.23 (m, 3H), 7.12(d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 7.00 (d, 1H, J 8.8 Hz),5.60 (dd, 1H, J 13.1, 2.8 Hz), 3.15 (dd, 1H, J −16.8, 13.1 Hz), 2.85(dd, 1H, J −16.8, 2.8 Hz).

b) 2-(3,5-Difluorophenyl)chroman-4,6-diol

2-(3,5-Difluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 800 mg of2-(3,5-difluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.87 (s, 1H), 7.21-7.17 (m, 3H), 6.88 (d, 1H, J 2.4 Hz), 6.64 (d, 1H,J 8.7 Hz), 6.55 (dd, 1H, J 2.4, 8.7 Hz), 5.47 (d, 1H, J 7.0 Hz), 5.17(d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).

c) 2-(3,5-Difluorophenyl)chroman-6-ol

2-(3,5-Difluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of2-(3,5-difluorophenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ:8.82 (s, 1H), 7.20-7.14 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J2.9 Hz), 6.50 (dd, 1H, J 8.6, 2.9 Hz), 5.05 (dd, 1H, J 9.8, 2.2 Hz),2.88 (ddd, 1H, J −16.7, 10.8, 5.9 Hz), 2.62 (ddd, 1H, J −16.7, 8.9, 5.0Hz), 2.15 (m, 1H), 1.93 (m, 1H).

d) 2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 340 mg of 2-(3,5-difluorophenyl)chroman-6-ol. Theproduct was purified on preparative TLC-plate covered with silica gelusing toluene-ethyl acetate as an eluant and then crystallised from2-propanol. ¹H NMR (400 MHz, d₆-DMSO) δ:9.04 (d, 1H, J 2.9 Hz), 8.60(dd, 1H, J 9.1, 2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd,1H, J 10.0, 2.1 Hz), 2.97 (ddd, 1H, J −16.9, 10.9, 5.7 Hz), 2.76 (ddd,1H, J −16.9, 8.4, 4.7 Hz), 2.22 (m, 1H), 1.99 (m, 1H).

Example 14 2-[2-(2.5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(2,5-Difluorophenyl)-6-hydroxychroman-4-one

2-(2,5-Difluorophenyl)-6-hydroxychroman-4-one was prepared as describedfor 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) startingfrom 3.0 g of 2′,5′-dihydroxyacetophenone and 2.57 ml of2,5-difluorobenzaldehyde. The product was recrystallised from aceticacid. ¹H NMR (300 MHz, d₆-DMSO) δ: 9.46 (s, 1H), 7.53 (m, 1H), 7.36-7.30(m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d,1H, J 8.8 Hz), 5.76 (dd, 1H, J 13.6, 2.7 Hz), 3.26 (dd, 1H, J −16.8,13.6 Hz), 2.76 (dd, 1H, J −16.8, 2.7 Hz).

b) 2-(2,5-Difluorophenyl)chroman-4,6-diol

2-(2,5-Difluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1.0 g of2-(2,5-difluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.87 (s, 1H), 7.39-7.22 (m, 3H), 6.89 (d, 1H, J 2.8 Hz), 6.63 (d, 1H,J 8.7 Hz), 6.56 (dd, 1H, J 8.7, 2.8 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.35(d, 1H, J 11.2 Hz), 4.89 (m, 1H), 2.28 (m, 1H), 1.95 (m, 1H).

c) 2-(2,5-Difluorophenyl)chroman-6-ol

2-(2,5-Difluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 420 mg of2-(2,5-difluorophenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ:8.82 (s, 1H), 7.34-7.22 (m, 3H), 6.71-6.51 (m, 3H), 5.20 (m, 1H), 2.93(m, 1H), 2.68 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H).

d) 2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 100 mg of 2-(2,5-difluorophenyl)chroman-6-ol. Theproduct was recrystallised from 2-propanol. ¹H NMR (400 MHz, CDCl₃) δ:9.07 (dd, 1H, J 2.8, 0.4 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.26 (m,1H), 7.05-6.91 (m, 6H), 5.35 (dd, 1H, J 10.3, 1.5 Hz), 3.04 (ddd, 1H, J−16.9, 11.7, 6.0 Hz), 2.82 (ddd, 1H, J −16.9, 5.2, 3.0 Hz), 2.29 (m,1H), 2.01 (m, 1H).

Example 15 2-[2-(3-Bromophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(3-Bromophenyl)-6-hydroxychroman-4-one

2-(3-Bromophenyl)-6-hydroxychroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4one in Example 9(a) starting from3.0 g of 2′,5′-dihydroxyacetophenone and 2.3 ml of 3-bromobenzaldehyde.The product was recrystallised from acetic acid. ¹H NMR (300 MHz,d₆-DMSO) δ: 9.41 (s, 1H), 7.50 (m, 1H), 7.59-7.53 (m, 2H), 7.39 (m, 1H),7.12 (d, 1H, J 2.9 Hz), 7.05 (dd, 1H, J 8.8, 2.9 Hz), 6.98 (d, 1H, J 8.8Hz), 5.57 (dd, 1H, J 13.0, 2.9 Hz), 3.12 (dd, 1H, J −16.9, 13.0 Hz),2.81 (dd, 1H, J −16.9, 2.9 Hz).

b) 2-(3-Bromo-phenyl)-chroman-4,6-diol

2-(3-Bromophenyl)-chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1.0 g of2-(3-bromophenyl)-6-hydroxychroman-4-one. ¹H NMR (300 MHz, d₆-DMSO) δ:8.83 (s, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.46 (m, 1H), 7.37 (m, 1H),6.88 (d, 1H, J 2.9 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.9Hz), 5.42 (d, 1H, J 7.0 Hz), 5.14 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.29(m, 1H), 1.84 (m, 1H).

c) 2-(3-Bromophenyl)chroman-6-ol

2-(3-Bromophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 700 mg of2-(3-bromophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.81 (s,1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 6.67-6.48(m, 3H), 5.01 (m, 1H), 2.87 (m, 1H), 2.63 (m, 1H), 2.12 (m, 1H), 1.92(m, 1H).

d) 2-[2-(3-Bromophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(3-Bromophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 339 mg of 2-(3-bromophenyl)chroman-6-ol. The productwas filtered through silica gel using toluene-ethyl acetate as an eluantand then crystallised from 2-propanol. ¹H NMR (400 MHz, CDCl₃) δ: 9.04(d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.66 (bs, 1H), 7.55 (m,1H), 7.48 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H, J 9.2 Hz), 7.01-6.93 (m,3H), 5.17 (dd, 1H, J 10.1, 2.2 Hz), 2.97 (m, 1H), 2.72 (m, 1H), 2.20 (m,1H), 2.00 (m, 1H).

Example 16 2-[2-(4-Ethylphenyl)chroman-6-yloxy]-5-nitropyridine a)2-(4-Ethylphenyl)-6-hydroxychroman-4-one

2-(4-Ethylphenyl)-6-hydroxychroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from1.0 g of 2′,5′-dihydroxyacetophenone and 0.8 ml of 4-ethylbenzaldehyde.The product was recrystallised from acetic acid. ¹H NMR (400 MHz,d₆-DMSO) δ: 7.43 (d, 2H, J 8.1 Hz), 7.25 (d, 2H, J 8.1 Hz), 7.11 (d, 1H,J 3.1 Hz), 7.03 (dd, 1H, J 8.9, 3.1 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.51(dd, 1H, J 13.0, 2.9 Hz), 3.15 (dd, 1H, J −16.9, 13.0 Hz), 2.75 (dd, 1H,J −16.9, 2.9 Hz), 2.62 (q, 2H, J 7.5 Hz), 1.18 (t, 3H, J 7.5 Hz).

b) 2-(4-Ethylphenyl)chroman-4,6-diol

2-(4Ethylphenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of2-(4-ethylphenyl)-6-hydroxychroman-4one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.81 (s, 1H), 7.34 (d, 2H, J 8.0 Hz), 7.22 (d, 2H, J 8.0 Hz), 6.88 (d,1H, J 2.8 Hz), 6.57 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6, 2.8 Hz),5.39 (d, 1H, J 7.1 Hz), 5.06 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.61 (q,2H, J 7.6 Hz), 2.29 (m, 1H), 1.84 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).

c) 2-(4-Ethylphenyl)chroman-6-ol

2-(4-Ethylphenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 425 mg of2-(4-ethyl-phenyl)chroman-4,6-diol. The product was purified usingheptane-ethyl acetate (3:1) as an eluant. ¹H NMR (400 MHz, CD₃OD) δ:7.26 (d, 2H, J 8.2 Hz), 7.13 (d, 2H, J 8.2 Hz), 6.65 (d, 1H, J 8.6 Hz),6.55 (dd, 1H, J 8.6, 2.8 Hz), 6.51 (d, 1H, J 2.8 Hz), 4.83 (dd, 1H, J10.1, 2.3 Hz), 2.84 (m, 1H), 2.62 (m, 1H), 2.59 (q, 2H, J 7.6 Hz), 2.03(m, 1H), 1.93 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).

d) 2-[2-(4-Ethylphenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(4-Ethylphenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 205 mg of 2-(4-ethylphenyl)chroman-6-ol. The productwas recrystallised from a mixture of 2-propanol and acetone. ¹H NMR (400MHz, CDCl₃) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz),7.36 (d, 2H, J 8.1 Hz), 7.24 (d, 2H, J 8.1 Hz), 7.20 (d, 1H, J 9.1 Hz),7.00 (d, 1H, J 2.7 Hz), 6.96 (dd, 1H, J 8.8, 2.7 Hz), 6.89 (d, 1H, J 2.7Hz), 5.11 (dd, 1H, J 10.1, 2.2 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.62 (q,2H, J 7.5 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.19 (t, 3H, J 7.5 Hz).

Example 17 2-(3-Methyl-2-phenylchroman-6-yloxy)-5-nitropyridine a)6-Hydroxy-3-methyl-2-phenylchroman-4-one

6-Hydroxy-3-methyl-2-phenylchroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from2.0 g of 2,5-dihydroxypropiophenone and 1.63 ml of benzaldehyde. Theproduct was purified by column chromatography using heptane-ethylacetate (3:1) as an eluant. ¹H NMR (300 MHz, d₆-DMSO) δ: 9.37 (s, 1H),7.53 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (d, 1H, J 3.1 Hz), 7.02 (dd, 1H, J8.9, 3.1 Hz), 6.89(d, 1H, J 8.9 Hz), 5.17 (d, 1H, J 12.3), 3.18 (dq, 1H,J 12.3, 6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).

b) 3-Methyl-2-phenylchroman-4,6diol

3-Methyl-2-phenylchroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of6-hydroxy-3-methyl-2-phenylchroman-4-one. ¹H NMR (300 MHz, d₆-DMSO) δ:8.79 (s, 1H), 7.42-7.33 (m, 5H), 6.88 (bs, 1H), 6.53 (m, 2H), 5.37 (d,1H, J 8.0 Hz), 4.70 (d, 1H, J 10.6 Hz), 1.94 (m, 1H), 0.73 (d, 3H, J 6.7Hz).

c) 3-Methyl-2-phenylchroman-6-ol

3-Methyl-2-phenylchroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 605 mg of3-methyl-2-phenylchroman-4,6-diol. 1H NMR (400 MHz, CD₃OD) δ: 8.77 (s,1H), 7.41-7.33 (m, 5H), 6.59-6.48 (m, 3H), 4.56 (d, 1H, J 9.2 Hz), 2.73(dd, 1H, J −16.5, 5.0 Hz), 2.54 (dd, 1H, J −116.5, 5.8 Hz), 2.11 (m,1H), 0.72 (d, 3H, J 6.6 Hz).

d) 2-(3-Methyl-2-phenylchroman-6-yloxy)-5-nitropyridine

2-(3-Methyl-2-phenylchroman-6-yloxy)-5nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 600 mg of 3-methyl-2-phenylchroman-6-ol. The productwas purified by column chromatography using heptane-2-propanol (20:1) asan eluant. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.59(dd, 1H, J 9.1, 2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, 1H, J 9.1 Hz), 7.00(d, 1H, J 2.6 Hz), 6.95 (dd, 1H, J 8.7, 2.6 Hz), 6.86 (d, 1H, J 8.7 Hz),4.73 (d, 1H, J 9.3Hz), 2.85 (dd, 1H, J −16.7, 5.0 Hz), 2.64 (dd, 1H, J−16.5, 10.9 Hz), 2.18 (m, 1H), 0.77 (d, 3H, J 6.7 Hz).

Example 18 3-Methyl-6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one

Methyl-6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 200 mg of 6-hydroxy-3-methyl-2-phenylchroman-4-one.The product was purified by column chromatography using heptane-ethylacetate (2:1) as an eluant and then crystallised from a mixture of2-propanol and acetone. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.03 (d, 1H, J 2.9Hz), 8.64 (dd, 1H, J 9.1, 2.9 Hz), 7.59-7.56 (m, 3H), 7.50-7.32 (m, 4H),7.30 (d, 1H, J 9.1 Hz), 7.18 (d, 1H, J 8.9 Hz), 5.38 (d, 1H, J 12.5 Hz),3.36 (dd, 1H, J 12.5, 6.9 Hz), 0.86 (d, 3H, J 6.9 Hz).

Example 19 2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(2-Fluorophenyl)-6-hydroxychroman-4-one

2-(2-Fluorophenyl)-6-hydroxychroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from2.0 g of 2′,5′-dihydroxyacetophenone and 1.4 ml of 2-fluorobenzaldehyde.The product was recrystallised from acetic acid. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.45 (s, 1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.32-7.25 (m, 2H),7.14 (d, 1H, J 3.0 Hz), 7.04 (dd, 1H, J 8.9, 3.0 Hz), 6.95 (d, 1H, J 8.9Hz), 5.77 (dd, 1H, J 13.5, 2.8 Hz), 3.26 (dd, 1H, J −16.9, 13.5 Hz),2.76 (dd, 1H, J −16.9, 2.8 Hz).

b) 2-(2-Fluorophenyl)chroman-4,6-diol

2-(2-Fluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1.19 g of2-(2-fluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.85 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.28-7.21 (m, 2H), 6.89 (d,1H, J 2.9 Hz), 6.60 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz),5.46 (d, 1H, J 6.9 Hz), 5.35 (d, 1H, J 10.6 Hz), 4.89 (m, 1H), 2.26 (m,1H), 1.98 (m, 1H).

c) 2-(2-Fluorophenyl)chroman-6-ol

2-(2-Fluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 800 mg of2-(2-fluorophenyl)chroman-4,6diol. ¹H NMR (300 MHz, d₆-DMSO) δ: 7.50 (m,1H), 7.39 (m, 1H), 7.26-7.19 (m, 2H), 6.63 (m, 1H), 6.53-6.50 (m, 2H),5.21 (dd, 1H, J, 10.2, 2.3 Hz), 2.98 (ddd, 1H, J −16.9, 11.2, 6.0 Hz),2.66 (ddd, 1H, J −16.9, 5.0, 2.9 Hz), 2.11 (m, 1H), 1.99 (m, 1H).

d) 2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 390 mg of 2-(2-fluorophenyl)chroman-6-ol. The productwas purified by column chromatography using heptane-ethyl acetate (4:1)as an eluant. ¹H NMR (400 MHz, CDCl₃) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60(dd, 1H, J 9.1, 2.8 Hz), 7.56 (m, 1H), 7.43 (m, 1H), 7.30-7.22 (m, 2H),7.20 (d, 1H, J 9.1 Hz), 7.02 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.7, 2.8Hz), 6.91 (d, 1H, J 8.7 Hz), 5.37 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (ddd,1H, J −17.0, 11.5, 6.0 Hz), 2.82 (ddd, 1H, J −17.0, 5.1, 2.8 Hz), 2.18(m, 1H), 2.08 (m, 1H).

Example 202-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine a)1-[2,5-Bis(benzyloxy)phenyl]ethanone

A mixture of 1-(2,5-dihydroxyphenyl)ethanone (3.16 g), benzyl chloride(7.04 g), potassium carbonate (12.4 g) and 18-Crown-6 (30 mg) in2-butanone (50 ml) was heated under reflux for 5 hrs. After cooling theprecipitate was filtered off. The filtrate was evaporated to drynessunder reduced pressure and ether (50 ml) was added to it. The solutionwas washed twice with dilute sodium hydroxide solution, twice withdilute hydrochloric acid, dried over sodium sulphate and substantiallyevaporated to dryness under reduced pressure. The residue was trituratedwith cold n-heptane (30 ml), and the precipitate was filtered off withsuction filtration giving after drying 2.85 g of1-[2,5-Bis(benzyloxy)phenyl]ethanone. ¹H NMR (400 MHz, DMSO-d₆) δ=2.50(s, 3H), 5.08 (s, 2H), 5.18 (s, 2H), 7.20-7.50 (m, 13H).

b) Acetic Acid 2,5-bis(benzyloxy)phenyl Ester

A solution of 1-[2,5-bis(benzyloxy)phenyl]ethanone (2.25 g) andperacetic acid 40% (1.63 ml) in acetic acid (5.4 ml) was stirred at 60°C. for 1 h. After cooling to room temperature the precipitated productwas collected by filtration, washed with cold ether and dried underreduced pressure. Acetic acid 2,5-bis(benzyloxy)phenyl ester wasrecrystallized from 2-propanol. Yield is 1.87 g. ¹H NMR (DMSO-d₆) 2.23(s, 1H), 5.03 (s, 2H), 5.05 (s, 2H), 6.84-7.44 (m, 13H).

c) 2,5-Bis(benzyloxy)phenol

A solution of acetic acid 2,5-bis(benzyloxy)phenyl ester (1.85 g) and 5Msodium hydroxide solution (10.6 ml) in ethanol (11 ml) was heated underreflux for 6.5 hrs. After ethanol was evaporated under reduced pressurethe clear solution was made acidic with diluted hydrochloric acid. Theprecipitated product was collected by filtration, washed with cold waterand dried under reduced pressure. Yield is 0.56 g. ¹H NMR (DMSO-d₆)δ=4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J=3.1, 8.8 Hz, 1H), 6.49(d,J=3.1 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 7.28-7.46 (m, 10H), 9.1 (br s,1H).

d) 2-[2,5-Bis(benzyloxy)phenoxy]-1-phenylethanone

A mixture of 2,5-bis(benzyloxy)phenol (0.28 g), 2-bromoacetophenone(0.22 g), potassium hydrogen-carbonate (0.25 g) and 18-Crown-6 (3 mg) inacetonitrile (4.2 ml) was stirred at 22° C. for one week. The mixturewas filtered and evaporated to dryness under reduced pressure. Theresidue was triturated with the mixture of ether (8.2 ml) and water (1.4ml) at the ice bath temperature. The product was collected byfiltration, washed with cold ether and dried under reduced pressure.Yield is 0.14 g. ¹H NMR (DMSO-d₆) δ=4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s,2H), 6.51 (dd, J=8.9, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.94 (d,J=8.9 Hz, 1H), 7.28-8.03 (m, 15H).

e) 2-[2,5-Bis(benzyloxy)phenoxy]-1-phenylethanol

To the solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanone (0.14g) in methanol (0.5 ml) and tetrahydrofuran (1.9 ml) was added at the 0°C. temperature sodium borohydride (6.5 mg). The reaction was stirred 15minutes at 0° C. and 2 hrs at 22° C. temperature. After adding water (5ml) methanol and tetrahydrofuran were evaporated off. After the residuewas stirred at 22° C. 0.5 hr the product was filtered, washed with coldwater and dried under reduced pressure. Yield is 0.09 g. ¹H NMR(DMSO-d₄) δ=4.05 (m, 2H), 4.91 (m, 1H), 4.95 (s, 2H), 5.01 (s, 2H), 5.59(d, J=4.7 Hz, 1H), 6.47 (dd, J=2.8, 8.8 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H),6.89 (d, J=8.8 Hz, 1H), 7.24-7.45 (m, 15H).

f) 2-(2-Hydroxy-2-phenylethoxy)benzene-1,4-diol

A solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanol (3.9 g) inethanol (175 ml) was hydrogenated in the presence of 10% palladium oncharcoal (100 mg) at 30 psi. The catalyst was removed by filtration andthe solvent was evaporated under reduced pressure. The residue wasrecrystallized from the mixture of toluene-ethyl acetate 8:1 (15 ml).The yield of 2-(2-Hydroxy-2-phenylethoxy)-benzene-1,4-diol is 1.2 g. ¹HNMR (DMSO-d₆) δ=3.79 (dd, J=9.6, 8.3 Hz, 1H), 4.00 (dd, J=9.6, 3.6 Hz,1H), 4.94 (ddd, J=3.6, 8.3, 3.9 Hz, 1H), 5.66 (d, J=3.9 Hz, 1H), 6.18(dd, J=8.5, 2.3 Hz, 1H), 6.34 (d, J=2.3, 1H), 6.57 (d, J=8.5, 1H),7.26-7.47 (m, 5H), 7.97 (s, 1H), 8.66 (s, 1H).

g) 2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-ol

A solution of 2-(2-hydroxy-2-phenylethoxy)benzene-1,4-diol (1.2 g) intoluene (75 ml) was heated with Amberlyst 15 catalyst (0.5 g) underreflux for 7 hrs. After filtering the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel (toluene/ethyl acetate/acetic acid=8:1:1). The yield of2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol is 0.5 g. ¹H NMR (DMSO-d₆)δ=4.02 (dd, J=8.5, 11.4 Hz, 1H), 4.35 (dd, J=2.3, 11.4 Hz, 1H), 5.11(dd, J=8.5, 2.3 Hz, 1H), 6.29 (dd, J=2.8, 8.5 Hz, 1H), 6.32 (d, J=2.8Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 7.36-7.47 (m, 5H), 8.99 (s, 1H).

h) 2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine

A solution of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg),2-chloro-5-nitropyridine (56 mg) and potassium carbonate (52 mg) indimethylformamide (1.0 ml) was stirred at 120° C. for 2 hrs. Aftercooling the mixture water (10 ml) was added and the precipitated productwas filtered, washed with water and 2-propanol and dried under reducedpressure. Yield is 60 mg and mp 163-170° C. ¹H NMR (DMSO-d₆) δ=4.16 (dd,J=8.5, 11.6 Hz, 1H), 4.47 (dd, J=11.6, 2.6 Hz, 1H), 5.28 (dd, J=2.6, 8.5Hz, 1H), 6.75 (dd, J=2.6, 8.8 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.05 (d,J=8.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd,J=2.8, 9.1 Hz, 1H), 9.05 (d, J=2.8 Hz, 1H).

Example 21 2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy-3-nitropyridine

2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-3-nitropyridine wasprepared in the same way as2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine abovefrom 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and2-chloro-3-nitropyridine (56 mg). Yield is 30 mg and mp <60° C. ¹H NMR(DMSO-d₆) δ=4.16 (dd, J=8.6, 11.4 Hz, 1H), 4.46 (dd, J=11.4, 2.5 Hz,1H), 5.27 (dd, J=2.5, 8.6 Hz, 1H), 6.73 (dd, J=2.5, 8.6 Hz, 1H), 6.85(d, J=2.5 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 7.34-7.52 (m, 6H), 8.43 (dd,J=1.9, 4.8 Hz, 1H), 8.55 (dd, J=7.8, 1,9 Hz, 1H).

Example 222-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-trifluoromethylpyridine

2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)5-trifluoromethylpyridinewas prepared in the same way as2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine abovefrom 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and2-chloro-5-(trifluoromethyl)pyridine (64 mg). Yield is 50 mg and mp104-110° C. ¹H NMR (DMSO-d₆) δ=4.15 (dd, J=8.3, 11.4Hz, 1H), 4.46 (dd,J=2.3, 11.4 Hz, 1H), 5.27 (dd, J=2.3, 8.3 Hz, 1H), 6.72 (dd, J=2.8, 8.8Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8Hz, 1H), 7.39-7.52 (m, 5H), 8.20 (dd, J=8.8, 2.6 Hz, 1H), 8.58 (d, J=2.6Hz, 1H).

Example 235-Nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine a)6-Methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one

A mixture of palladium(II) acetate (0.57 g),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (1.91 g) and potassiumtert-butoxide (4.15 g) in dry toluene was stirred under argon for 10minutes. Bromobenzene (5.34 g) and 6-methoxy-1-tetralone (3.0 g)solvated in dry toluene were added and the mixture was stirred at 100°C. for 2 h. The reaction mixture was cooled to room temperature andpoured into saturated aqueous ammonium chloride and extracted with ethylether. Organic extract was washed with brine, dried and evaporated. Thecrude product was purified by flash chromatography on silica gel usingtoluene and toluene-ethyl acetate (9:1) as an eluant. ¹H NMR (400 MHz,d₆-DMSO) δ: 7.87 (d, 1H, J 7.8 Hz), 7.16-7.33 (m, 5H), 6.91-6.94 (m,2H), 3.85 (s, 3H), 3.82-3.88 (m, 1H), 3.06-3.14 (m, 1H), 2.92-2.98 (m,1H), 2.23-2.38 (m, 2H).

b) 6-Hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one

6-Methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (1.0 g) was refluxedwith 47% HBr (20 ml) until disappearance of the starting material. Themixture was poured into water and extracted with ethyl acetate. Ethylacetate was dried and evaporated. The product was recrystallised fromtoluene. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.35 (s, 1H), 7.79 (d, 1H, J 8.6Hz), 7.15-7.33 (m, 5H), 6.75 (dd, 1H, J 8.6, 2.4 Hz), 6.68 (d, 1H, J 2.3Hz), 3.79-3.85 (m, 1H), 2.99-3.06 (m, 1H), 2.83-2.90 (m, 1H), 2.19-2.33(m, 2H).

c) 6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol

To a solution of 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (50mg) in trifluoroacetic acid was added triethylsilane (98 mg). Themixture was heated at 60° C. for 3 h. Solvent was evaporated, wateradded to the residue and the mixture extracted with ethyl acetate.Organic extract was dried and evaporated. ¹H NMR (400 MHz, d₆-DMSO) δ:9.02 (s, 1H), 7.18-7.32 (m, 5H), 6.87 (d, 1H, J 7.9), 6.50-6.53 (m, 2H),2.68-2.92 (m, 5H), 1.94-1.99 (m, 1H), 1.81-1.89 (m, 1H).

d) 5-Nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine

6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg),2-chloro-5-nitropyridine (21 mg) and potassium fluoride (23 mg) in drydimethylformamide were heated at 120° C. until disappearance of thestarting material. Water and 1 N HCl were added and the mixtureextracted with ethyl acetate. Ethyl acetate was washed with brine andwater, dried and evaporated. The product was recrystallised fromtoluene. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd,1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m,5H), 1.87-2.04 (m, 2H).

Example 246-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1 one

6-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1-one wasprepared as described for5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine inExample 23(d) using 50 mg6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one, 33 mg2-chloro-5-nitropyridine and 37 mg potassium fluoride. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0, 2.9), 8.01 (d,1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m,1H), 3.15-3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31(m, 1H).

Example 25 3-N-Acetylamino-4-(2-phenylchroman-6-yloxy)-anisole

3-Amino-4-(2-phenylchroman-6-yloxy)-anisole of Example 3 (0.174 g) wasdissolved in 2 ml of dry pyridine under nitrogen. Acetic anhydride (0.15ml) and 10 mol-% of 4-(N,N-dimethylamino)pyridine (DMAP) were added andthe reaction solution was stirred for 2.5 hours at room temperature andquenched with addition of 1 ml of H₂O. Toluene was added into thereaction mixture and evaporated to dryness. Toluene evaporation wasrepeated. Product was purified by column chromatography(CH₂Cl₂:EtOAc/98:2). ¹H-NMR (400 MHz; d₆-DMSO): δ 9.38 (s, 1H), 7.68 (s,1H), 7.47-7.25 (m, 5H), 6.85-6.66 (m, 4H), 6.63 (dd, 1H, J=8.8 Hz, J=3.0Hz), 5.07 (dd, 1H, J=9.9 Hz, J=1.9 Hz), 3.71 (s, 3H), 3.0-2.85 (m, 1H),2.75-2.62 (s, 1H), 2.20-2.10 (m, 1H), 2.05 (s, 3H), 2.08-1.90 (m, 1H).

Example 26 5-Amino-2-(2-phenylchroman-6-yloxy-pyridine

5-Nitro-2-(2-phenylchroman-6-yloxy)-pyridine of Example 1 (2.26 g) wasdissolved in 350 ml of glacial acetic acid. Zinc powder (8.48 g) wasadded in few portions due to exothermic reaction. The mixture wasstirred at room temperature for 2 hours and filtered. The zinc waswashed with glacial acetic acid. The acid was evaporated and toluene wasadded and evaporated again. A product mixture was dissolved in CH₂Cl₂and washed with 1M NaOH. Water phase was further washed with CH₂Cl₂.Both organic fractions were combined and dried over Na₂SO₄. Product waspurified by column chromatography. 1H-NMR (400 MHz; d₆-DMSO): δ 7.52 (d,1H, J=2.8 Hz), 7.46-7.30 (m, 5H), 7.05 (dd, 1H, J=8.6 Hz, J=3.0 Hz),6.82-6.72 (m, 3H), 6.69 (d, 1H, J=8.6 Hz), 5.08 (dd, 1H, J=10.0 Hz;J=2.1 Hz), 5.00 (s, 2H), 3.00-2.87 (m, 1H), 2.74-2.64 (m, 1H), 2.19-2.10(m, 1H), 2.05-1.91 (m, 1H).

Example 27 5-N-Acetylamino-2-(2-phenylchroman-6-yloxy pyridine

5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine of Example 26 (0.955 g) wasdissolved in 8 ml of dry pyridine under nitrogen. DMAP (0.038 g) wasadded. AcCl (0.26 ml) was added at room temperature into the reactionsolution dropwise because of vigorous and exothermic reaction. Thereaction was stirred for 90 minutes at room temperature and quenchedwith slow addition of 1 ml of H₂O. 50 ml of toluene was added andevaporated to dryness. Toluene evaporation was repeated twice. Brownishproduct mixture was purified with column chromatography(EtOAc:CH₂Cl₂/60:40) to give of crystalline slightly yellowish product.The product was further purified with recrystallization from MeOH:H₂O(71:29). The precipitate was filtered and washed with 2×10 ml of icecold MeOH:H₂O (1:1). ¹H-NMR (400 MHz; (d₆-DMSO): δ 10.04 (s, 1H), 8.27(d, 1H, J=2.4 Hz), 8.01 (dd, 1H, J=8.9 Hz; J=2.8 Hz), 7.47-7.31 (m, 5H),6.93 (d, 1H, J=8.9 Hz), 6.85 (d, 2H, J=6.8 Hz), 6.84 (s, 1H), 5.11 (dd,1H, J=10.1 Hz; J=2.2 Hz), 3.02-2.90 (m, 1H), 2.71 (ddd, 1H, J=16.8 Hz;J=5.1 Hz, J=1.8 Hz), 2.22-2.11 (m, 1H), 2.08-1.92 (m, 1H).

Example 28 5-N,N-Diacetylamino-2-(2-phenylchroman-6-yloxy)-pyridine

5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine of Example 26 (0.40 g) wasdissolved in 1.5 ml of dry pyridine under nitrogen. DMAP (10 mol-%) andAc₂O (1.0 ml) were added and the solution was stirred at roomtemperature for 2.5 hours. Toluene was added and evaporated to dryness.Toluene evaporation was repeated twice. Product was purified by columnchromatography (EtOAc:CH₂Cl₂/60:40). ¹H-NMR (400 MHz; d₆-DMSO): δ 8.05(d, 1H, J=2.6 Hz), 7.78 (dd, 1H, J=8.7 Hz; J=2.6 Hz), 7.48-7.31 (m, 5H),7.07 (d, 1H, J=8.9 Hz), 6.99-6.85 (m, 3H), 5.13 (dd, 1H, J=10.1 Hz;J=1.9 Hz), 3.05-2.92 (m, 1H), 2.78-2.70 (m, 1H), 2.21 (s, 6H), 2.25-2.12(m, 1H), 2.08-1.94 (m, 1H).

Example 29 2-(2-Phenylchroman-6-yloxy)-aniline a)2-Nitro-1-(2-phenylchroman-6-yloxy)-benzene

6-Hydroxyflavane (0.150 g) was dissolved in dry DMSO (5 ml) undernitrogen. KI (0.166 g) and KOH (0.074g) were added and solution wasstirred at room temperature for 15 minutes. 2-Chloro-1-nitrobenzene(0.104 g) was added and the solution was stirred at +90° C. for 2.5hours. Cooled solution was taken up with CH₂Cl₂ and washed with H₂O and2M NaOH. Phases were separated and water phase was washed CH₂Cl₂. Allorganic phases were combined and washed with 1M HCl and then H₂O (untilpH˜7) and brine. Solution was dried over Na₂SO₄ and purified withfiltration through the small silica column in CH₂Cl₂:n-heptane (60:40).¹H-NMR (300 MHz; d₆-DMSO): δ 8.01 (dd, 1H, J=8.1 Hz; J=1.7 Hz), 7.69 (m,1H), 7.50-7.31 (m, 5H), 7.31-7.24 (m, 1H), 7.04 (dd, 1H, J=8.5 Hz; J=1.2Hz), 6.92 (s, 1H), 6.90 (s, 2H), 5.12 (dd, 1H, J=10.1 Hz; J=2.3 Hz),2.95 (ddd, 1H, J=16.9 Hz; J=11.2 Hz, J=5.8 Hz), 2.73 (ddd, 1H, J=16.9Hz; J=3.2 Hz, J=1.7 Hz), 2.25-2.10 (m, 1H), 2.08-1.90 (m, 1H).

b) 2-(2-Phenylchroman-6-yloxy)-aniline

2-Nitro-1-(2-phenylchroman-6-yloxy)-benzene (0.160 g) was mostlydissolved in 30 ml of glacial acetic acid. Zinc powder (1.190 g) wasadded in few portions and the mixture was stirred for 90 minutes at roomtemperature. The zinc was filtered and washed with glacial acetic acidand evaporated. The evaporation residue was taken up with toluene andevaporated again. The residue was dissolved in CH₂Cl₂ and washed with IMNaOH. NaOH solution was further washed with CH₂Cl₂. Both organicfractions were combined and dried over Na₂SO₄. The purification of thecrude product was done by elution in CH₂Cl₂ through a small silicacolumn. ¹H-NMR (400 MHz; d₆-DMSO): δ 7.45-7.28 (m, 5H), 6.89-6.83 (m,1H), 6.80 (d, 1H, J=8.5 Hz), 6.77 (dd, 1H, J=8.0 Hz; J=1.7 Hz),6.73-6.67 (m, 3H), 6.54-6.48 (m, 1H), 5.06 (dd, 1H, J=10.1 Hz; J=2.3Hz), 4.85 (s, 2H), 2.99-2.87 (m, 1H), 2.73-2.61 (m, 1H), 2.19-2.09 (m,1H), 2.03-1.90 (m, 1H).

Example 30 5-Trifluoromethyl-2-(2-phenylchroman-6-yloxy)-aniline a)2-Nitro-1-(2-phenylchroman-6-yloxy)-4trifluoromethylbenzene

2-Nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene wasprepared as described for ²-nitro-1-(2-phenylchroman-6-yloxy)-benzene inExample 29(a) except that 6-hydroxyflavane (0.339 g) was used in 7 ml ofdry DMSO under nitrogen. Also KI (0.374 g) and KOH (0.168 g) and4-chloro-3-nitro-1-trifluoromethylbenzene (0.24 ml) were added insimilar manner. Product was purified by column chromatography(CH₂Cl₂:n-heptane/60:40). ¹H-NMR (300 MHz; d₆-DMSO): δ 8.44 (d, 1H,J=2.1 Hz), 7.99 (dd, 1H, J=9.0 Hz; J=2.2 Hz), 7.51-7.29 (m, 5H), 7.15(d, 1H, J=8.7 Hz), 7.09-6.91 (m, 3H), 5.15 (dd, 1H, J=10.1 Hz; J=2.3Hz), 3.08-2.90 (m, 1H), 2.83-2.68 (m, 1H), 2.25-2.11 (m, 1H), 2.09-1.91(m, 1H).

b) 5-Trifluoromethyl-2-(2-phenylchroman-6-yloxy)-aniline

2-Nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.311 g)was reduced in 25 ml of glacial acetic acid with zinc (1.48 g) asdescribed for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29. Productwas purified by column chromatography (CH₂Cl₂:n-heptane/70:30 as theeluant). ¹H-NMR (300 MHz; d₆-DMSO): δ 7.48-7.28 (m, 5H), 7.06 (d, 1H,J=2.2 Hz), 6.86 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 6.85-6.56 (m, 3H), 6.72(d, 1H, J=8.4 Hz), 5.40 (s, 2H), 5.10 (dd, 1H, J=10.0 Hz; J=2.3 Hz),3.04-2.87 (m, 1H), 2.78-2.65 (m, 1H), 2.24-2.10 (m, 1H), 2.08-1.89 (m,1H).

Example 31 5-Amino-2-(2-phenylchroman-6-yloxy)-aniline a)2,4-Dinitro-1-(2-phenylchroman-6-yloxy)-benzene

2,4-Dinitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared asdescribed for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example29(a) except that 6-hydroxyflavane (0.226 g) was used in 5 ml of dryDMSO under nitrogen. Also KI (0.249 g) and KOH (0.112g) and2,4-dinitrochlorobenzene (0.210 mg) were added in similar manner.Product was purified by column chromatography (CH₂Cl₂:n-heptane/75:25 asthe eluant). ¹H-NMR (400 MHz; d₆-DMSO): δ 8.88 (d, 1H, J=2.8 Hz), 8.45(dd, 1H, J=9.4 Hz, J=2.9 Hz), 7.48-7.30 (m, 5H), 7.14 (d, 1H, J=9.3 Hz),7.10 (d, 1H, J=2.8 Hz), 7.05 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 6.98 (d, 1H,J=8.7 Hz), 5.16 (dd, 1H, J=10.2 Hz, J=2.1 Hz), 3.08-2.93 (m, 1H),2.83-2.71 (m, 1H), 2.25-2.13 (m, 1H), 2.08-1.94 (m, 1H).

b) 5-Amino-2-(2-phenylchroman-6-yloxy)-aniline

2,4-Dinitro-1-(2-phenylchroman-6-yloxy)-benzene (0.04 g) was dissolvedin 12 ml of glacial acetic acid and zinc (0.131 g) was added. Thereaction stirred at room temperature for 30 minutes. Workup was done asdescribed for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29. Productwas purified by column chromatography (CH₂Cl₂:Et₃N /96:4 as the eluant).¹H-NMR (300 MHz; d₆-DMSO): δ 7.48-7.28 (m, 5H), 6.74 (d, 1H, J=8.8 Hz),6.63 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 6.57 (d, 1H, J=2.8 Hz), 6.49 (d, 1H,J=8.4 Hz), 6.02 (d, 1H, J=2.6 Hz), 5.81 (dd, 1H, J=8.4 Hz, J=2.6 Hz),5.03 (dd, 1H, J=10.0 Hz, J=2.3 Hz), 4.62 (s, 2H), 4.48 (s, 2H),2.99-2.82 (m, 1H), 2.71-2.57 (m, 1H), 2.20-2.06 (m, 1H), 2.03-1.86 (m,1H)

Example 32 5-Cyano-2-(2-phenylchroman-6-yloxy)-aniline a)4-Cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene

4-Cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared asdescribed for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example29(a) except that 6-hydroxyflavane (0.453 g) was used in 10 ml of dryDMSO under nitrogen. Also KI (0.498 g) and KOH (0.224 g) and4-chloro-3-nitro benzonitrile (0.365 mg) were added in similar manner.Product was purified by column chromatography (CH₂Cl₂:n-heptane/90:10 asthe eluant). ¹H-NMR (400 MHz; d₆-DMSO): δ 8.64 (d, 1H, J=2.0 Hz), 8.06(dd, 1H, J=8.8 Hz, J=2.1 Hz), 7.08 (d, 1H, J=8.8 Hz), 7.07-6.93 (m, 3H),5.15 (dd, 1H, J=10.1 Hz, J=2.1 Hz), 3.05-2.91 (m, 1H), 2.82-2.70 (m,1H), 2.24-2.12 (m, 1H), 2.08-1.92 (m, 1H).

b) 5-Cyano-2-(2-phenylchroman-6-yloxy)-aniline

4-Cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene (0.155 g; 0.4 mmol)was reduced to the corresponding aniline as described for2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 40 ml ofglacial acetic acid and 0.93 g of zinc powder were used. Product waspurified by column chromatography (100% CH₂Cl₂ as the eluant). ¹H-NMR(300 MHz; d₆-DMSO): δ 7.57-7.28 (m, 5H), 7.06 (d, 1H, J=2.0 Hz),6.95-6.78 (m, 4H), 6.65 (d, 1H, J=8.3 Hz), 5.46 (s, 2H), 5.11 (dd, 1H,J=10.0 Hz, J=2.1 Hz), 3.03-2.88 (m, 1H), 2.78-2.66 (m, 1H), 2.23-2.10(m, 1H), 2.08-1.89 (m, 1H).

Example 33 N-Acetyl-2-(2-Penylchroman-6-yloxy)-aniline

2-(2-Penylchroman-6-yloxy)-aniline (0.093 g) was dissolved in 1 ml ofdry pyridine under nitrogen. DMAP (10 mol-%) and acetic acid anhydride(0.1 ml) were added and the solution was stirred for 4 hours at roomtemperature followed with quenching with 0.5 ml of H₂O. The solution wasevaporated to dryness and toluene was added and evaporated again.Toluene evaporation was repeated. Product was purified by columnchromatography (CH₂Cl₂:i-PrOH/98:2 as the eluant) and recrystallizedfrom 0.5 ml of heated absolute ethanol by cooling and adding 0.5 ml of¹H-NMR (400 MHz; d₆-DMSO): δ 9.43 (s, 1H), 7.96 (m, 1H), 7.48-7.30 (m,5H), 7.08-6.99 (m, 2H), 6.89-6.74 (m, 4H), 5.10 (dd, 1H, J=9.9, J=2.0),3.03-2.88 (m, 1H), 2.76-2.65 (m, 1H), 2.21-2.11 (m, 1H), 2.10-1.91 (m,1H), 2.06 (s, 3H).

Example 34 3-Nitro-2-(2-phenylchroman-6-yloxy)-pyridine

6-Hydroxyflavane (0.150 g) was dissolved in 3 ml of dry DMF undernitrogen. KF (0.117 g) was added and the solution was stirred for 30minutes at +120° C. The solution was cooled a bit and2-chloro-3-nitropyridine was added (0.212 g) and stirred for 7 hours at+120° C. and overnight at room temperature. The reaction mixture wastaken up with EtOAc and 1M HCl and water were added and phasesseparated. Organic phase was washed with water and pH was adjusted to 7with 1M NaOH. Organic phase was washed with water, brine and dried overNa₂SO₄. Product was purified by column chromatography(CH₂Cl₂:n-heptane/80:20). ¹H-NMR (400 MHz; d₆-DMSO): δ 8.55 (dd, 1H,J=7.9 Hz, J=1.7 Hz), 8.42 (dd, 1H, J=4.9 Hz, J=1.7 Hz), 7.51-7.29 (m,6H), 7.02-6.92 (m, 2H), 6.88 (d, 1H, J=8.7 Hz), 5.14 (dd, 1H, J=10.0 Hz,J=2.1 Hz), 3.05-2.92 (m, 1H), 2.78-2.68 (m, 1H), 2.22-2.13 (m, 1H),2.07-1.95 (m, 1H).

Example 353-Amino-5-(trifluoromethyl)-2-(2-phenylchroman-6-yloxy)-aniline a)2,6-Dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene

2,6-Dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene wasprepared as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene inExample 29(a) except that 6-hydroxyflavane (0.453 g) was used in 10 mlof dry DMSO under nitrogen. Also KI (0.498 g) and KOH (0.224 g) and4-chloro-3,5-dinitro benzotrifluoride (0.541 mg) were added in similarmanner. ¹H-NMR (400 MHz; d₆-DMSO): δ 8.87 (s, 2H), 7.46-7.29 (m, 5H),6.89-6.75 (m, 4H), 5.09 (dd, 1H, J=10.3 Hz, J=2.1 Hz), 2.98-2.85 (m,1H), 2.75-2.62 (m, 1H), 2.19-2.08 (m, 1H), 2.03-1.88 (m, 1H).

b) 3-Amino-5-(trifluoromethyl)-2-(2-phenylchroman-6-yloxy)-aniline

2,6-Dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.198g; 0.43 mmol) was reduced to corresponding diamino compound as describedfor 2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 25 mlof glacial acetic acid and 1.525 g of metallic zinc powder were used.Product was purified by column chromatography (100% CH₂Cl₂ as theeluant). ¹H-NMR (400 MHz; d₆-DMSO): δ 7.45-7.28 (m, 5H), 6.76 (d, 1H,J=8.8 Hz), 6.65 (dd, 1H, J=8.7 Hz, J=3.0 Hz), 6.62 (d, 1H, J=2.8 Hz),5.04 (dd, 1H, J=10.0 Hz, J=2.1 Hz), 4.98 (s, 4H), 2.98-2.86 (m, 1H),2.70-2.60 (m, 1H), 2.18-2.09 (m, 1H), 2.00-1.88 (m, 1H).

Example 36 5-Succinimido-2-(2-phenylchroman-6-yloxy)-pyridine

5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine of Example 26 (0.16 g) wasdissolved in 7.5 ml of glacial acetic acid under nitrogen. Succinicanhydride (0.0563 g) was added and the solution refluxed 60 minutes andsolution was cooled and evaporated to dryness. Toluene (25 ml) was addedand evaporated again to dryness. Product was purified by columnchromatography (CH₂Cl₂:i-PrOH /95:5 as the eluant. ¹H-NMR (400 MHz;d₆-DMSO): δ 8.03 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=8.7 Hz, J=2.6 Hz),7.48-7.31 (m, 5H), 7.10 (d, 1H, J=8.7 Hz), 6.95 (d, 1H, J=2.6 Hz), 6.92(dd, 1H, J=8.7 Hz, J=2.7 Hz), 6.88 (d, 1H, J=8.6 Hz), 5.13 (dd, 1H,J=10.2 Hz, J=2.2 Hz), 3.05-2.92 (m, 1H), 2.84-6.68 (m, 1H), 2.79 (s,4H), 2.22-2.12 (m, 1H), 2.08-1.93 (m, 1H).

Example 375-(O,O′-Diacetyl-L-tartaricimido)-2-(2-phenylchroman-6-yloxy)-pyridine

5-(O,O′-Diacetyl-L-tartaricimido)-2-(2-phenylchroman-6-yloxy)-pyridinewas prepared as described for5-succinimido-2-(2-phenylchroman-6-yloxy)-pyridine in Example 36 exceptthat 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine (0.318 g) and(+)-diacetyl-L-tartaric acid anhydride (0.227 g) were refluxed in 15 mlof glacial acetic acid for 60 minutes. ¹H-NMR (400 MHz; d₆-DMSO): δ 8.10(d, 1H, J=2.6 Hz), 7.79 (dd, 1H, J=8.7 Hz, J=2.6 Hz), 7.49-7.30 (m, 5H),7.13 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=2.5 Hz), 6.93 (dd, 1H, J=8.7 Hz,J=2.7 Hz), 6.88 (d, 1H, J=8.7 Hz), 6.08 (s, 2H), 5.13 (dd, 1H, J=10.1Hz, J=1.9 Hz), 3.06-2.92 (m, 1H), 2.80-2.69 (m, 1H), 2.23-2.12 (m, 1H),2.18 (s, 6H), 2.08-1.93 (m, 1H).

Example 38 5-Nitro-2-(2-phenylindan-5-yloxy)-pyridine a)3-(4-Methoxyphenyl)-2-phenylacrylic Acid

Triethylamine was added to solution of p-anisaldehyde (10 g) andphenylacetic acid (10 g) in acetic anhydride (25 ml). Reaction mixturewas stirred at 90° C. for 8 h. Reaction mixture was cooled and water(600 ml) solution of potassium carbonate (81 g) was added. Afteraddition reaction mixture was heated at 60° C. for an hour. Beforeneutralising with concentrated hydrochloric acid the reaction mixturewas cooled below 10° C. Precipitate was filtered and washed with water.¹H-NMR (400 MHz, d₆-DMSO): 12.6 (bs, 1H), 7.67 (s, 1H), 7.4-7.3 (m, 3H),7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8-6.7 (m, 2H), 3.70 (s, 3H).(M)⁺=254 (100%).

b) 3-(4-Methoxyphenyl)-2-phenylpropionic Acid

13 g of 3-(4-methoxyphenyl)-2-phenylacrylic acid was dissolved to 600 mlof ethyl acetate and 2.6 g of 10% palladium on charcoal was added underinert atmosphere. Starting material was hydrogenated at room temperatureto give quantitative yield of 3-(4-methoxyphenyl)-2-phenylpropionicacid. ¹H-NMR (400 MHz, d₆-DMSO): 12.3 (bs, 1H), 7.32-7.20 (m, 5H),7.1-7.0 (m, 2H), 6.8-6.7 (m, 2H), 3.79 (dd, 1H, J 6.9, 8.7 Hz), 3.70 (s,3H), 3.22 (dd, 1H, J 8.7, 13.7 Hz), 2.87 (dd, 1H, J 6.9, 13.7 Hz).

c) 6-Methoxy-2-phenylindan-1-one

To solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (4.6 g) in drymethylenechloride (26 ml) was added two drops of dry DMF.Thionylchloride (3 ml) was added and reaction mixture was stirred at 40°C. for 4 h. Solvent was evaporated under vacuum. Precipitate wasdissolved to methylenechloride. Solution was cooled to 0-3° C. Thissolution and aluminium chloride (2.5g) were mixed slowly over 4 hourskeeping temperature under 4° C. After mixing reaction mixture wasstirred at room temperature for 2 h. Reaction was quenched by pouring todilute ice cold hydrochloric acid. Layers were separated and watersolution was extracted with methylenechloride. Combined organic layerswere washed with water, dried and evaporated. Crude product wastriturated to give 2.9 g of 6-Methoxy-2-phenylindan-1-one. ¹H-NMR (400MHz, d₆-DMSO): 7.56 (d, 1H), 7.35-7.23 (m, 4H), 7.18-7.13 (m, 3H), 4.02(dd, 1H, J 3.9, 8.0 Hz), 3.82 (s, 3H), 3.61 (dd, 1H, J 8.0, 17.2 Hz),3.11 (dd, 1H, J 3.9, 17.2 Hz).

d) 5-Methoxy-2-phenylindane

5-Methoxy-2-phenylindane was prepared as described for2-phenylchroman-6-ol in Example 1(a) using 600 mg of6-methoxy-2-phenylindan-1-one. ¹H-NMR (400 MHz, d₆-DMSO): 7.32-7.27 (m,4H), 7.21-7.18 (m, 1H), 7.13 (d, 1H, J 8.2 Hz), 6.83 (d, 1H, J 2.4 Hz),6.72 (dd, 1H, J 2.4, 8.2 Hz), 3.72 (s, 3H), 3.64 (k, 1H, J 8.5 Hz), 3.23(dt, 2H, J 8.5, 15.9 Hz), 2.92 (m, 2H).

e) 2-Phenylindan-5-ol

Mixture of 5-methoxy-2-phenylindane (200 mg) and concentrated HBr (4 ml)was refluxed for 5.5 h. Reaction mixture was allowed to cool to roomtemperature and 20 ml of ice water and it was extracted withmethylenechloride. The combined organic layers were washed with brineand dried with Na₂SO₄. The solvents were evaporated to give2-phenylindan-5-ol. ¹H-NMR (400 MHz, d₆-DMSO): 9.05 (bs, 1H), 7.3-7.28(m, 4H), 7.26-7.15 (m, 1H), 7.0 (d, 1H, J 8.1 Hz), 6.64 (d, 1H, J 1.9Hz), 6.55 (dd, 1H, J 1.9, 8.1 Hz), 3.60 (k, 1H, J 8.6 Hz), 3.18 (m, 2H),2.86 (dt, 2H, J 8.6, 16 Hz).

f) 5-Nitro-2-(2-phenylindan-5-yloxy)pyridine

5-Nitro-2-(2-phenylindan-5-yloxy)pyridine was prepared as described for2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 107 mg of2-phenylindan-5-ol. ¹H-NMR (400 MHz, d₆-DMSO): 9.04 (d, 1H, J 2.9 Hz),8.61 (dd, 1H, J 2.9, 9.1 Hz), 7.38-7.28 (m, 5H), 7.24-7.20 (m, 2H), 7.11(d, 1H, J 2.2 Hz), 7.00 (dd, 1H, J 2.2, 8.0 Hz), 3.72 (k, 1H, J 8.9 Hz),3.36-3.28 (m, 2H), 3.01 (dd, 2H, J 8.9, 15.3 Hz).

Example 39 5-Methoxy-2-(2-phenylindan-5-yloxy)phenylamine a)5-(4-Methoxy-2-nitrophenoxy)-2-phenylindane

5-(4Methoxy-2-nitrophenoxy)-2-phenylindan was prepared as described for6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using 575mg of 2-phenylindan-5-ol. ¹H-NMR (400 MHz, d₆-DMSO): 7.60 (d, 1H, J 3.1Hz), 7.35-7.28 (m, 5H), 7.25-7.16 (m, 3H), 6.86 (d, 1H, J 2.3 Hz), 6.78(dd, 1H, J 2.3, 8.2 Hz), 3.84 (s, 3H), 3.67 (k, 1H, J 8.3 Hz), 3.25 (dd,2H, J 8.3, 15.7 Hz), 2.95 (m, 2H). (M)⁺=361 (60%), 209 (100%)

b) 5-Methoxy-2-(2-phenylindan-5-yloxy)phenylamine

5-Methoxy-2-(2-phenylindan-5-yloxy)phenylamine was prepared as describedfor 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(b)using 200 mg of 5-(4-methoxy-2-nitrophenoxy)-2-phenylindane. ¹H-NMR (400MHz, d₆-DMSO): 7.33-7.27 (m, 4H), 7.23-7.18 (m, 2H), 6.82 (d, 1H, J 8.4Hz), 6.81 (s, 1H), 6.77 (dd, 1H, J 2.3, 8.4 Hz), 6.69 (d, 1H, J 2.3 Hz),6.48 (bd, 1H, J 6.4 Hz), 3.71 (s, 3H), 3.66 (k, 1H, J 8.3 Hz), 3.24 (dd,2H, J 8.3, 15.6 Hz), 2.93 (m, 2H). (M)⁺=331 (100%)

Example 40 2-[2-(3-Fluorophenyl)-indan-5-yloxy]-5-methoxyphenylamine a)2-(3-Fluorophenyl)indan-5-ol

2-(3-Fluorophenyl)indan-5-ol was prepared as described for2-phenylindan-5-ol in Example 25(a-e) using 5 g of 3-fluorophenylaceticacid. ¹H-NMR (400 MHz, d₆-DMSO): 9.09 (s, 1H), 7.37-7.29 (m, 1H),7.14-7.7.09 (m, 2H), 7.02-6.98 (m, 2H), 6.64 (d, 1H, J 1.7 Hz), 6.55(dd, 1H, J 2.3, 8.1 Hz), 3.63 (k, 1H, J 8.3 Hz), 3.24-3.12 (m, 2H),2.94-2.79 (m, 2H).

b) 5-Methoxy-2-[2-(3-fluorophenyl)indan-5-yloxy]phenylamine

5-Methoxy-2-[2-(3-fluorophenyl)indan-5-yloxy]phenylamine was prepared asdescribed for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine inExample 3(a-b) using 500 mg of 2-(3-fluorophenyl)indan-5-ol. ¹H-NMR (400MHz, CDCl₃): 7.26-7.21 (m, 1H), 7.16 (d, 1H, J 2.9 Hz), 7.09 (d, 1H, J8.2 Hz), 7.02 (d, 1H, J 7.7 Hz), 6.96-6.88 (m, 4H), 6.83 (d, 1H, J 9.1Hz), 6.72 (dd, 1H, J 2.9, 9.1 Hz), 3.69 (s, 3H), 3.65 (k, 1H, J 8.8 Hz),3.26-3.19 (m, 2H), 2.94 (dd, 2H, J 8.8, 15.1 Hz).

Example 41 2-(2-Phenylindan-5-yloxy)phenylamine a)5-(2-Nitrophenoxy)-2-phenylindane

5-(2-nitrophenoxy)-2-phenylindane was prepared as described for6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using 200mg 2-phenylindan-5-ol and 150 mg of 1-chloro-2-nitrobenzene. ¹H-NMR (400MHz, d₆-DMSO): 8.04 (dd, 1H, J 1.6, 8.3 Hz), 7.68 (ddd, 1H, J 1.6, 7.4,8.3 Hz), 7.36-7.27 (m, 6H), 7.24-7.17 (m, 1H), 7.11 (dd, 1H, J 1.1, 8.4Hz), 6.98 (bd, 1H, J 2.3 Hz), 6.89 (dd, 1H, J 2.3, 8.1 Hz), 3.69 (k, 1H,J 8.5 Hz), 3.28 (dd, 2H J 8.5, 15.8 Hz), 3.05-2.95 (m, 2H).

b) 2-(2-Phenylindan-5-yloxy)phenylamine

2-(2-Phenylindan-5-yloxy)phenylamine was prepared as described for2-(2-phenylchroman-6yloxy)-phenylamine in Example 29(b) using 170 mg of5-(2-nitrophenoxy)-2-phenylindane. ¹H-N (400 MHz, d₆-DMSO): 7.32-7.27(m, 4H), 7.23-7.16 (m, 2H), 6.92-6.87 (m, 1H), 6.81-6.71 (m, 4H),6.56-6.53 (m, 1H), 4.85 (bs, 2H), 3.65 (k, 1H, J 8.3 Hz), 3.23 (dd, 2H,J 8.3, 15.5 Hz), 2.97-2.88 (m, 2H).

Example 422-(2-Phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine a)5-(2,6-Dinitro-4-trifluoromethylphenoxy)-2-phenylindan

Potassium-t-butoxide (117 mg) was added into a solution of2-phenylindan-5-ol (200 mg) in dry DMF (3 ml). After stirring resultingmixture at room temperature for 30 min4-chloro-3,5-dinitrobenzotrifluoride (275 mg) was added. Reactionmixture was stirred for a further three hours at 150° C. After coolinginto room temperature water and ethyl acetate was added into themixture. 1 M Hydrochloric acid was added into water layer and thesolution was extracted with ethyl acetate. Combined organic layers werewashed with water and brine, dried with Na₂SO₄ and evaporated.5-(2,6-Dinitro-4-trifluoromethylphenoxy)-2-phenylindan wasrecrystallised from ethanol. ¹H-NMR (400 MHz, d₆-DMSO): 8.89 (s, 2H),7.33-7.27 (m, 4H), 7.23-7.18 (m, 2H), 6.96 (d, 1H, J 2.5 Hz), 6.83 (dd,1H, J 2.5, 8.2 Hz), 3.67 (k, 1H, J 8.6 Hz), 3.27-3.19 (m, 2H), 2.97-2.89(m, 2H).

b) 2-(2-Phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine

2-(2-Phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine wasprepared as described for2-(2-phenylchroman-6-yloxy)-5-trifluoromethylbenzene-1,3-diamine inExample 35(b) using 230 mg of5-(2,6-dinitro-4-trifluoromethylphenoxy)-2-phenylindan. ¹H-NMR (300 MHz,d₆-DMSO): 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 7.14 (d, 1H, J 8.1 Hz),6.73-6.69 (m, 2H), 6.31 (s, 2H), 4.98 (s, 4H), 3.64 (k, 1H, J 8.5 Hz),3.26-3.18 (m, 2H), 2.96-2.86 (m, 2H).

Example 43 6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine a)6-Hydroxy-2-phenylchroman-4-one Oxime

Sodium hydroxide (122 mg) was added into a cooled solution of6-hydroxyflavanone (2 g) and hydroxylamine hydrochloride (900 mg) inethanol (5 ml) and water (2 ml). Resulting mixture was refluxed for 6hours and hydroxylamine hydrochloride (450 mg) and sodium hydroxide (61mg) were added after every 45 min. After cooling into room temperaturewater (23 ml) and concentrated hydrochloric acid (5.6 ml) were addedinto the mixture. Precipitate was filtered, washed with water and driedin vacuum. ¹H-NMR (400 MHz, d₆-DMSO): 11.3 (s, 1H), 9.11 (s, 1H),7.50-7.48 (m, 2H), 7.43-7.33 (m, 3H), 7.21 (d, 1H, J 2.9 Hz), 6.80 (d,1H, J 8.8 Hz), 6.72 (dd, 1H, J 2.9, 8.8 Hz), 5.07 (dd, 1H, J 3.2, 11.9Hz), 3.28 (dd, 1H, J 3.2, 17.1 Hz), 2.64 (dd, 1H, J 11.9,17.1 Hz).

b) 4-Amino-2-phenylchroman-6-ol

A solution of 6-hydroxy-2-phenylchroman-4-one oxime (2.07 g) in1,2-dimethoxy ethane (20 ml) was added into a cooled solution oftitanium(IV)chloride (1.9 ml) and sodium borohydride (1.29 g) in1,2-dimethoxy ethane (20 ml). Resulting mixture was stirred for afurther 4 hours at room temperature. Reaction was quenched with ice andpH was adjusted to 2-3. Resulting mixture was extracted with toluene.Water layer was made alkaline with solution of sodium hydroxide. Darkprecipitate was filtered and washed with methanol. Methanol washingswere evaporated to dryness, dissolved to water and neutralised andfinally precipitate was filtered. Mixture of diastereomers of4-amino-2-phenylchroman-6-ol was isolated as its hydrochloride salt.(M)⁺=241 (4.4%), 224 (10%), 137 (100%).

c) 6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine

6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine was prepared asdescribed for 2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 100mg of hydrochloride salt of 4-amino-2-phenylchroman-6-ol. Mixture ofdiastereomers of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylaminewas isolated as its hydrochloride salt.(M)⁺=363 (22%), 259 (100%), 242(70%), 224 (64%), 223 (62%).

Example 44 N-[6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide

Acetic anhydride (60 μl) was added into a cooled solution of6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine hydrochloride (100mg) and pyridine (41 μl) in dry DMF. Resulting mixture was stirred for afurther 20 hours at 0° C. Reaction was quenched with ice water andneutralised. Resulting mixture was extracted with dichloromethane, driedwith Na₂SO₄ and evaporated. Mixture of diastereomers ofN-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide wasrecrystallised from dichloromethane. (M)⁺=405 (24%), 301 (14%), 259(100%), 242 (55%), 224 (96%).

Example 45Dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-amine a)4-N,N-Dimethylamino-2-phenylchroman-6-ol

Sodium cyanoborohydride (274 mg) was added into a solution of free baseof 4-amino-2-phenylchroman-6-ol (263 mg) and 37% formaldehyde (1.4 ml)in acetonitrile (15 ml). After 30 min pH was adjusted to 6-7 with aceticacid. Resulting mixture was stirred at room temperature over night.Reaction mixture was evaporated to dryness, precipitate was dissolved to10% solution of potassium hydroxide and extracted with methylenechloride. Combined organic layers were dried and evaporated to give4-N,N-dimethylamino-2-phenylchroman-6-ol as mixture of diastereomers.¹H-NMR (400 MHz, d₆-DMSO): 8.79 (bs, 1H, major and minor), 7.5-7.3 (m,5H, major and minor), 6.96 (d, 1H, J 2.8 Hz, major), 6.75 (d, 1H, J 2.9Hz, minor), 6.69 (d, 1H, 8.7 Hz, minor), 6.63-6.60 (m, 1H, major andminor), 6.53 (dd, 1H, J 2.8, 8.7 Hz, major), 5.17 (dd, 1H, J 2.7, 9.7Hz, minor), 5.04 (d, 1H, J 10.7 Hz, major), 4.17 (dd, 1H, J 5.7, 11.4Hz, major), 3.35 (m, 1H, minor), 2.24 (s, 3H, minor), 2.21 (s, 3H,major), 2.2-1.7 (m, 2H, major and minor).

b) Dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-amine

N,N-Dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-amine wasprepared as described for 2-phenylchroman-6-yloxy)pyridine in Example1(b) using 220 mg of 4-N,N-dimethylamino-2-phenylchroman-6-ol.N,N-Dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchromanyl-4-yl]-aminewas isolated as a mixture of diastereomers. (M)⁺=391 (8%), 347 (8%), 346(8%), 287 (68%), 147 (100%).

Example 46 N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]methanesulfonamide

Pyridine (77 μl) and methanesufonyl chloride (32 μl) were added into acooled solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (121 mg)in dry THF (2 ml). After stirring resulting mixture at 0° C. foradditional 2 hours 1 M hydrochloric acid was added. Solution wasextracted with ethyl acetate. Combined organic layers were dried withNa₂SO₄ and evaporated.N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]methanesulfonamide wasrecrystallised from diethyl ether. ¹H NMR (300 MHz, d₆-DMSO) δ: 9.64 (s,1H), 7.99 (d, 1H, J 2.8 Hz), 7.67 (dd, 1H, J 2.8, 8.8 Hz), 7.47-7.31 (m,5H), 6.97 (d, 1H, J 8.8 Hz), 6.89-6.82 (m, 3H), 5.12 (dd, 1H, J 2.2,10.1 Hz), 3.0-2.9 (m, 1H), 2.98 (s, 3H), 2.77-2.69 (m, 1H), 2.20-2.13(m, 1H), 2.04-1.96 (m, 1H).

Example 47 1-Methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea

Solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (150 mg) andmethyl isothiocyanate (94 μl) in ethanol was refluxed for 10 hours.After cooling solvents were evaporated. Crude product of1-methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea waspurified by column chromatography (5% methanol in dichloromethane). ¹HNMR (400 MHz, d₆-DMSO) δ: 9.45 (bs, 1H), 8.02 (d, 1H, J 2.7 Hz), 7.81(dd, 1H, J 2.7, 8.8 Hz), 7.70 (bs, 1H), 7.47-7.38 (m, 4H), 7.36-7.32 (m,1H), 6.94-6.86 (m, 4H), 5.12 (dd, 1H J 2.3, 10.1 Hz), 2.98-2.93 (m, 1H),2.90 (d, 3H, J 4.3 Hz), 2.76-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.15-1.99(m, 1H).

Example 48 3-[6-(5-Nitropyridin-2-yloxy)chroman-2-yl]phenol a)6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one was prepared as described for

6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.50 (bs,1H), 9.41 (bs, 1H), 7.22-7.17 (m, 1H), 7.11 (d, 1H, J 3.0 Hz), 7.03 (dd,1H J 3.0, 8.9 Hz), 6.64 (d, 1H, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-6.73(m, 1H), 5.46 (dd, 1H J 2.9, 12.7 Hz), 3.09 (dd, 1H, J 12.7, 16.9 Hz),2.75 (dd, 1H, J 2.9, 16.9 Hz).

b) 2-(3-Hydroxyphenyl)chroman-4,6-diol

2-(3-Hydroxyphenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:9.43 (bs, 1H), 8.88 (bs, 1H), 7.19-7.15 (m, 1H), 6.87 (d, 1H, J 2.7 Hz),6.84-6.82 (m, 2H), 6.72-6.69 (m, 1H), 6.58 (d, 1H, J 8.7 Hz), 6.53 (dd,1H, J 2.7, 8.7), 5.01 (d, 1H, J 11.3 Hz), 4.86 (dd, 1H, J 6.2, 10.8 Hz),2.25-2.19 (m, 1H), 1.88-1.75 (m, 1H).

c) 2-(3-Hydroxyphenyl)chroman-6-ol

2-(3-Hydroxyphenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from2-(3-hydroxyphenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.38(s, 1H), 8.77 (s, 1H), 7.17-7.13 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.67(m, 1H), 6.62 (d, 1H, J 8.6 Hz), 6.52-6.47 (m, 2H), 4.89 (dd, 1H, J 2.1,9.9Hz), 2.86-2.82 (m, 1H), 2.65-2.59 (m, 1H), 2.09-2.04 (m, 1H),1.91-1.85 (m, 1H).

d) 3-[6-(5-Nitropyridin-2-yloxy)chroman-2-yl]phenol

3-[6-(5-Nitropyridin-2-yloxy)chroman-2-yl]phenol was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(3-hydroxyphenyl)chroman-6-ol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.44 (s, 1H), 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 2.8,9.1 Hz), 7.21-7.16 (m, 2H), 7.00-6.94 (m, 2H), 6.91-6.84 (m, 3H),6.73-6.70 (m, 1H), 5.06 (dd, 1H, J 2.1, 9.9 Hz), 2.99-2.92 (m, 1H),2.75-2.69 (m, 1H), 2.17-2.01 (m, 1H), 2.00-1.93 (m, 1H).

Example 49 6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was preparedas described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example26 starting from 830 mg of2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example14(d)). ¹H NMR (300 MHz, d₆-DMSO) δ: 7.51 (d, 1H, J 2.9 Hz), 7.36-7.25(m, 3H), 7.05 (dd, 1H, J 8.6, 2.9 Hz), 6.84-6.68 (m, 4H), 5.29 (d, 1H, J8.6), 4.99 (s, 2H), 2.96 (m, 1H), 2.72 (m, 1H), 2.14 (m, 1H), 2.01 (m,1H).

Example 50N-{6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide wasprepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 370 mg of6-[2-(2,5-difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example49). The product was purified on preparative TLC-plate covered withsilica gel using ethyl acetate-heptane (4:1) as an eluant. ¹H NMR (400MHz, CD₃OD) δ: 8.27 (d, 1H, J 2.7 Hz), 8.01 (dd, 1H, J 8.9, 2.7 Hz),7.26 (m, 1H), 7.13 (m, 1H), 7.08 (m, 1H), 6.92-6.84 (m, 4H), 5.32 (dd,1H, J 10.1, 1.6 Hz), 2.99 (ddd, 1H, J −16.9, 11.4, 5.9 Hz), 2.78 (ddd,1H, J −16.9, 8.4, 5.1 Hz), 2.26 (m, 1H), 2.13 (s, 3H), 1.97 (m, 1H).

Example 51 6-[2-(2-Fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(2-Fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26starting from 240 mg of2-[2-(2-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 19(d)).¹H NMR (400 MHz, d₆-DMSO) δ: 7.52 (m, 1H), 7.51 (d, 1H, J 3.0 Hz), 7.41(m, 1H), 7.28-7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.81-6.73 (m,3H), 6.70 (d, 1H, J 8.6 Hz), 5.31 (dd, 1H, J 10.3, 2.2 Hz), 5.00 (s,2H), 2.98 (m, 1H), 2.72 (m, 1H), 2.15 (m, 1H), 2.06 (m, 1H).

Example 52N-{6-[2-(2-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(2-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide wasprepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 220 mg of6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 51).The product was recrystallised from a mixture of methanol and diethylether. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.06 (s, 1H), 8.27 (d, 1H, J 2.7Hz), 8.01 (dd, 1H, J 8.8, 2.7 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 7.29-7.23(m, 2H), 6.93 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.34 (dd, 1H, J10.2, 2.2 Hz), 3.01 (m, 1H), 2.75 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H),2.04 (s, 3H).

Example 53N-{6-[2-(2-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamide

N-{6-[2-(2-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamidewas prepared as described forN-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methane sulfonamide inExample 46 starting from 400 mg of6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 51).The product was crystallised from a mixture of methanol and diethylether. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.67 (s, 1H), 7.99 (d, 1H, J 2.8Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 7.29-7.23(m, 2H), 6.98 (dd, 1H, J 8.8 Hz), 6.92-6.84 (m, 3H), 5.35 (dd, 1H, J10.4, 2.3 Hz), 3.01 (m, 1H), 2.99 (s, 3H), 2.76 (m, 1H), 2.16 (m, 1H),2.04 (m, 1H).

Example 54 6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26starting from 2.34 g of2-[2-(3-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 9(d)). ¹HNMR (400 MHz, d₆-DMSO) δ: 7.51 (d, 1H, J 3.0 Hz), 7.44 (m, 1H),7.30-7.25 (m, 2H), 7.16 (m, 1H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.83-6.73(m, 3H), 6.69 (d, 1H, J 8.6 Hz), 5.13 (dd, 1H, J 10.0, 3.0 Hz), 5.00 (s,2H), 2.93 (ddd, 1H, −16.8, 10.5, 5.3 Hz), 2.68 (ddd, 1H, J −16.8, 8.0,4.4 Hz), 2.18 (m, 1H), 1.96 (m, 1H).

Example 55N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide wasprepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 300 mg of6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 54). Theproduct was recrystallised from a mixture of methanol and diethyl ether.¹H NMR (400 MHz, d₆-DMSO) δ: 10.09 (s, 1H), 8.28 (d, 1H, J 2.7 Hz), 8.02(dd, 1H, J 8.8, 2.7 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H),6.93 (d, 1H, J 8.8 Hz), 6.89-6.83 (m, 3H), 5.16 (dd, 1H, J 10.1, 2.1Hz), 2.95 (ddd, 1H, J −16.5, 11.0, 6.5 Hz), 2.71 (ddd, 1H, J −16.5, 8.7,4.4 Hz), 2.19 (m, 1H), 2.04 (s, 3H), 1.96 (m, 1H).

Example 56 6-(5-Aminopyridin-2-yloxy)-2-phenylchroman-4-one

6-(5-Aminopyridin-2-yloxy)-2-phenylchroman-4-one was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26starting from 100 mg of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one(Example 6). ¹H NMR (400 MHz, CD₃OD) δ: 7.62 (d, 1H, J 3.0 Hz),7.51-7.49 (m, 2H), 7.42-7.33 (m, 3H), 7.25-7.18 (m, 3H), 7.06 (d, 1H, J8.8 Hz), 6.76 (d, 1H, J 8.6Hz), 5.50 (dd, 1H, J 13.0, 2.9 Hz), 3.08 (dd,1H, −17.0, 13.0 Hz), 2.82 (dd, 1H, J −17.0, 2.9 Hz).

Example 57 Acetic Acid 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylEster

Acetanhydride (0.26 ml) was added dropwise into a solution of 100 mg of6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ol (Example 8(b)) in drypyridine. The reaction mixture was refluxed for 1½ hours. It was thenpoured in ice-water and extracted with ethyl acetate. The organic phasewas washed with 1 M HCl-solution, water and saturated NaCl-solution. Itwas then dried with MgSO₄ and evaporated to dryness. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.05 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8 Hz),7.52-7.35 (m, 5H), 7.23 (d, 1H, J 9.1 Hz), 7.14-7.10 (m, 2H), 6.98 (d,1H, J 8.5 Hz), 6.18 (dd, 1H, J 10.1, 6.4 Hz), 5.44(dd, 1H, J 11.4,1.4Hz), 2.51 (m, 1H), 2.15 (m, 1H), 2.05 (s, 3H).

Example 58 6-(2-Aminoethoxy)-2-phenylchroman-4-one Methane Sulfonate a)6-(2-Azidoethoxy)-2-phenylchroman-4-one

6-(2-Azidoethoxy)-2-phenylchroman-4-one was prepared as described for6-(2-azidoethoxy)-2-phenylchroman in example 4(a) starting from 1.0 g of6-hydroxy-flavanone. ¹H NMR (400 MHz, CD₃OD) δ: 7.53-7.51 (m, 2H),7.44-7.35 (m, 4H), 7.22 (dd, 1H, J 9.0, 3.1 Hz), 7.04 (d, 1H, J 9.0 Hz),5.51 (dd, 1H, J 13.1, 3.0 Hz), 4.17 (t, 2H, J 4.9 Hz), 3.60 (t, 2H, J4.9 Hz), 3.11 (dd, 1H, J −16.9, 13.1 Hz), 2.85 (dd, 1H, J −16.9, 3.0Hz).

b) 6-(2-Aminoethoxy)-2-phenylchroman-4-one Methane Sulfonate

6-(2-Aminoethoxy)-2-phenylchroman-4-one methane sulfonate was preparedas described for 2-(2-phenylchroman-6-yloxy)ethylamine methane sulfonatein Example 4 (b) starting from 6-(2-azidoethoxy)-2-phenylchroman-4-one.¹H NMR (400 MHz, d₆-DMSO) δ: 7.91 (bs, 3H), 7.55-7.54 (m, 2H), 7.46-7.37(m, 3H), 7.31 (d, 1H, J 3.1 Hz), 7.28 (dd, 1H, 8.8, 3.1 Hz), 7.12 (d,1H, 8.8 Hz), 5.63 (dd, 1H, 13.0, 3.0 Hz), 4.17 (t, 2H, J 5.1 Hz), 3.25(dd, 1H, J −16.9, 13.0 Hz), 3.23 (m, 2H), 2.86 (dd, 1H, J −16.9, 3.0Hz), 2.29 (s, 3H).

Example 59 2-(3-Bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(3-Bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4ol was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 215 mg of 2-(3-bromophenyl)chroman-4,6-diol (Example15(b)). The product was recrystallised from a mixture of 2-propanol andacetone. ¹H NMR (300 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.61 (dd,1H, J 9.1, 2.8 Hz), 7.69 (m, 1H), 7.58-7.50 (m, 2H), 7.40 (m, 1H), 7.25(d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.7 Hz),6.91 (d, 1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.8 Hz),4.97 (m, 1H), 2.36 (m, 1H), 1.94 (m, 1H).

Example 60 2-(2-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(2-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 315 mg of 2-(2-fluorophenyl)chroman-4,6-diol (Example19(b)). The product was recrystallised from a mixture of 2-propanol andacetone. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd,1H, J 9.1, 2.9 Hz), 7.61 (m, 1H), 7.43 (m, 1H), 7.31-7.24 (m, 3H), 7.23(d, 1H, J 9.1 Hz), 7.02 (dd, 1H, J 8.7, 3.1 Hz), 6.89 (d, 1H, J 8.7 Hz),5.69 (d, 1H, J 6.3 Hz), 5.55 (d, 1H, J 11.9 Hz), 5.00 (m, 1H), 2.33 (m,1H), 2.07 (m, 1H).

Example 61 2-(2,5-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(2,5-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) starting from 200 mg of2-(2,5-difluorophenyl)chroman-4,6-diol (Example 14(b)). The product waspurified on preparative TLC-plate covered with silica gel usingtoluene-ethyl acetate (4:1) as an eluant. ¹H NMR (400 MHz, CDCl₃) δ:9.03 (d, 1H, J 2.8 Hz), 8.50 (dd, 1H, J 9.1, 2.8 Hz), 7-36-7.33 (m, 2H),7.08-6.95 (m, 5H), 5.50 (d, 1H, J 11.1 Hz), 5.09 (m, 1H), 2.53 (m, 1H),2.05 (m, 1H).

Example 62 2-(3-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(3-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 890 mg of 2-(3-fluorophenyl)chroman-4,6-diol (Example9(b)). The product was purified by column chromatography using gradientelution with ethyl acetate-heptane (20%→33%) and then crystallised froma mixture of 2-propanol and acetone. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.04(d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.48 (m, 1H), 7.35-7.31(m, 2H), 7.26-7.19 (m, 3H), 7.02 (dd, 1H, J 8.8, 2.9 Hz), 6.91 (d, 1H, J8.8 Hz), 5.67 (d, 1H, J 6.4 Hz), 5.34 (d, 1H, J 10.4 Hz), 4.98 (m, 1H),2.36 (m, 1H), 1.99 (m, 1H).

Example 63 2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-ethoxyphenylamineHydrochloride a) 1-Chloro-4-ethoxy-2-nitrobenzene

4-Chloro-3-nitrobenzene (5.0 g) was dissolved in acetone and ethyliodide (2.5 ml) and potassium carbonate (4.4 g) were added. The reactionmixture was stirred at 40° C. for 4½ hours. After cooling to roomtemperature the mixture was filtered and the filtrate was evaporated todryness. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.64 (m, 2H), 7.27 (dd, 1H, J 9.0,3.1 Hz), 4.12 (q, 2H, J 7.0 Hz), 1.34 (t, 3H, 7.0 Hz).

b) 2-(2,5-Difluorophenyl)-6-(4-ethoxy-2-nitrophenoxy)chroman

320 mg of 2-(2,5-Difluorophenyl)chroman-6-ol (Example 14(c)) wasdissolved in dry DMF and potassium tert-butoxide (150 mg) was added. Theresulting mixture was stirred for 30 minutes and1-chloro-4-ethoxy-2-nitrobenzene (250 mg) was added. The reactionmixture was refluxed for 8 hours. After cooling to room temperature 1 MHCl-solution was added into the reaction mixture and it was extractedwith ethyl acetate. The combined organic extracts were washed with waterand saturated NaCl-solution. The product was purified by columnchromatography using heptane-ethyl acetate (3:1) as an eluant. ¹H NMR(300 MHz, CDCl₃) δ: 7.43 (d, 1H, J 2.9Hz), 7.25 (m, 1H), 7.08-6.97 (m,4H), 6.89-6.75 (m, 3H), 5.31 (d, 1H, J 9.1 Hz), 4.06 (q, 2H, J 7.0 Hz),2.97 (m, 1H), 2.74 (m, 1H), 2.26 (m, 1H), 1.98 (m, 1H), 1.44 (t, 3H, 7.0Hz).

c) 2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-ethoxyphenylamineHydrochloride

2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-ethoxyphenylaminehydrochloride was prepared as described for5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride inexample 3(b) starting from 120 mg of2-(2,5-difluorophenyl)-6-(4-ethoxy-2-nitrophenoxy)chroman. ¹H NMR (400MHz, CDCl₃) δ: 7.26-7.22 (m, 2H), 7.01-6.74 (m, 7H), 5.22 (d, 1H, J 9.1Hz), 3.90 (q, 2H, J 6.9 Hz), 2.90 (m, 1H), 2.68 (m, 1H), 2.19 (m, 1H),1.90 (m, 1H), 1.34 (t, 3H, 6.9 Hz).

Example 645-Nitro-2-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridine a)6-Hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one

6-Hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one was prepared asdescribed for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a)starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 2.1 ml of4-trifluoromethylbenzaldehyde. The product was purified by columnchromatography using heptane-ethyl acetate (2:1) as an eluant. Furtherpurification was carried out by column chromatography usingtoluene-ethyl acetate (4:1) as an eluant. Finally the product wascrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.47 (s, 1H),7.82-7.76 (m, 4H), 7.13 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz),6.99 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 12.9, 2.9 Hz), 3.16 (dd, 1H, J−16.9, 12.9 Hz), 2.86 (dd, 1H, J −16.9, 2.9 Hz).

b) 2-(4-Trifluoromethylphenyl)chroman-4,6-diol

2-(4-Trifluoromethylphenyl)chroman-4,6-diol was prepared as describedfor 2-phenylchroman-4,6-diol in Example 8(a) starting from 860 mg of2-(4-trifluoromethylphenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz,d₆-DMSO) δ: 8.86 (s, 1H), 7.77 (d, 2H, J 8.3 Hz), 7.68 (d, 2H, J 8.3Hz), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J8.7, 2.9 Hz), 5.45 (d, 1H, J 7.0 Hz), 5.26 (d, 1H, J 11.2 Hz), 4.90 (m,1H), 2.32 (m, 1H), 1.85 (m, 1H).

c) 2-(4-Trifluoromethylphenyl)chroman-6-ol

2-(4-Trifluoromethyl phenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 730 mg of2-(4-trifluoromethylphenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.82 (s, 1H), 7.75 (d, 2H, J 8.3 Hz), 7.65 (d, 2H, J 8.3 Hz), 6.67(d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz), 6.51 (dd, 1H, 8.6, 2.9 Hz),5.12 (d, 1H, J 8.3 Hz), 2.90 (m, 1H), 2.63 (m, 1H), 2.16 (m, 1H), 1.92(m, 1H).

d) 2-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) starting from 605 mg of2-(4-trifluoromethylphenyl)chroman-6-ol. The product was purified columnchromatography using 1.5% ethyl acetate in toluene as an eluant and thencrystallised from a mixture of 2-propanol and acetone. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.79(d, 2H, J 8.2 Hz), 7.70 (d, 1H, J 8.2 Hz), 7.21 (d, 1H, J 9.1 Hz), 7.01(dd, 1H, J 8.7, 2.7 Hz), 6.98 (d, 1H, J 2.7 Hz), 6.95 (d, 1H, 8.7 Hz),5.29 (dd, 1H, J 10.1, 2.0 Hz), 3.00 (ddd, 1H, J −16.9, 10.1, 5.8 Hz),2.4 (ddd, 1H, J −16.9, 8.4, 4.5 Hz), 2.24 (m, 1H), 1.99 (m, 1H).

Example 656-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine

6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine wasprepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine inExample 26 starting from 275 mg of2-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine (Example64(d)). ¹H NMR (400 MHz, d₆-DMSO) δ: 7.78 (d, 2H, J 8.4 Hz), 7.68 (d,2H, J 8.4 Hz), 7.52 (dd, 1H, J 2.9, 0.5 Hz), 7.06 (dd, 1H, 8.6, 2.9 Hz)6.84 (m, 1H), 6.77-6.75 (m, 2H), 6.70 (dd, 1H, J 8.6, 0.5 Hz), 5.23 (dd,1H, J 10.0, 2.0 Hz), 5.01 (s, 2H), 2.95 (ddd, 1H, −16.8, 11.1, 5.9 Hz),2.69 (ddd, 1H, J −16.8, 8.5, 4.8 Hz), 2.21 (m, 1H), 1.97 (m, 1H).

Example 66N-{6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-yl}acetamidewas prepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 140 mg of6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]-pyridin-3-ylamine(Example 65). ¹H NMR (400 MHz, d₆-DMSO) δ: 10.11 (s, 1H), 8.29 (d, 1H, J2.7 Hz), 8.02(dd, 1H, J 8.9, 2.7 Hz), 7.78 (d, 2H, J 8.3 Hz), 7.69 (d,2H, J 8.3 Hz), 7.17 (m, 1H), 6.94-6.86 (m, 3H), 5.66 (d, 1H, J 8.2 Hz),2.98 (m, 1H), 2.72 (m, 1H), 2.23 (m, 1H), 2.04 (s, 3H), 1.97 (m, 1H).

Example 67 N-{6-[2-(3-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methaneSulfonamide

N-{6-[2-(3-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamidewas prepared as described forN-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methanesulfonamide in Example46 starting from 300 mg of6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 54).The product was purified by passing through silica gel using ethylacetate-heptane (5:1) as an eluant. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.67(s, 1H), 7.99 (dd, 1H, J 2.8, 0.6 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz),7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 6.98 (dd, 1H, J 8.8, 0.6Hz), 6.90-6.88 (m, 3H), 5.16 (dd, 1H, J 10.0, 2.2 Hz), 2.99 (s, 3H),2.96 (m, 1H), 2.72 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H).

Example 68 2-(4-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol a)6-Hydroxy-2-(4-chlorophenyl)chroman-4-one

6-Hydroxy-2-(4-chlorophenyl)chroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from3.0 g of 2′,5′-dihydroxyacetophenone and 2.8 g of 4-chlorobenzaldehyde.The product was triturated from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ:9.46 (s, 1H), 7.56 (d, 2H, J 8.5 Hz), 7.45 (d, 2H, J 8.5 Hz), 7.11 (d,1H, J 2.8 Hz), 7.04 (dd, 1H, J 8.9, 2.8 Hz), 6.96 (d, 1H, J 8.9 Hz),5.58 (dd, 1H, J 13.1, 2.9 Hz), 3.15 (dd, 1H, J −16.8, 13.1 Hz), 2.79(dd, 1H, J −16.8, 2.9 Hz).

b) 2-(4-Chlorophenyl)chroman-4,6-diol

2-(4-Chlorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 375 mg of2-(4-chlorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.84 (s, 1H), 7.49-7.44 (m, 4H), 6.88 (d, 1H, J 2.8 Hz), 6.60 (d, 1H, J8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.8 Hz), 5.43 (bs, 1H), 5.14 (dd, 1H, J11.9, 1.6 Hz), 4.87 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H).

c) 2-(4-Chlorophenyl)-6-(S-nitropyridin-2-yloxy)chroman-4ol

2-(4-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 330 mg of 2-(4-chlorophenyl)chroman-4,6-diol. Theproduct was purified by column chromatography using heptane-ethylacetate (2:1) as an eluant. ¹H NMR (300 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.54-7.47 (m, 4H), 7.25 (d, 1H, J2.8 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.8 Hz), 6.89 (d,1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.6 Hz), 4.98 (m,1H), 2.34 (m, 1H), 1.94 (m, 1H).

Example 69 2-[2-(2.4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(2,4-Difluorophenyl)-6-hydroxychroman-4-one

2-(2,4-Difluorophenyl)-6-hydroxychroman-4-one was prepared as describedfor 2-(3-fluorophenyl)6-hydroxychroman-4-one in Example 9(a) startingfrom 3.0 g of 2′,5′-dihydroxyacetophenone and 1,6 ml of2,4-difluorobenzaldehyde. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.46 (s, 1H),7.73 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 7.13 (d, 1H, J 2.9 Hz), 7.04(dd, 1H, J 8.8, 2.9 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.74 (dd, 1H, J 13.5,2.8 Hz), 3.28 (dd, 1H, J −16.9, 13.5 Hz), 2.74 (dd, 1H, J −16.9, 2.8Hz).

b) 2-(2,4-Difluorophenyl)chroman-4,6-diol

2-(2,4-Difluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1,47 g of2-(2,4-difluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.86 (s, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 7.14 (m, 1H), 6.88 (d, 1H,J 2.7 Hz), 6.59 (d, 1H, J 8.9 Hz), 6.54 (dd, 1H, J 8.9, 2.7 Hz), 5.46(s, 1H), 5.32 (dd, 1H, J 11.9, 1.4 Hz), 4.88 (m, 1H), 2.24 (m, 1H), 1.99(m, 1H).

c) 2-(2,4-Difluorophenyl)chroman-6-ol

2-(2,4-Difluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 800 mg of2-(2,4-difluorophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ:8.83 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 7.13 (m, 1H), 6.63 (m, 1H),6.53-6.50 (m, 2H), 5.17 (dd, 1H, J 10.3, 2.3 Hz), 2.92 (ddd, 1H, J−17.0, 11.5, 5.8 Hz), 2.66 (ddd, 1H, J −17.0, 5.0, 2.7 Hz), 2.09 (m,1H), 1.98 (m, 1H).

d) 2-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 720 mg of 2-(2,4-difluorophenyl)chroman-6ol. ¹H NMR(400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.0, 3.0Hz), 7.61 (m, 1H), 7.31 (m, 1H), 7.21 (d, 1H, 9.0 Hz), 7.17 (m, 1H),7.02 (d, 1H, J 2.9 Hz), 6.97 (dd, 1H, J 8.9, 2.9 Hz), 6.91 (d, 1H, 8.9Hz), 5.34 (dd, 1H, J 9.9, 2.0 Hz), 3.03 (m, 1H), 2.78 (m, 1H), 2.17 (m,1H), 2.07 (m, 1H).

Example 70 6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was preparedas described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example26 starting from 845 mg of2-[2-(2,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example69(d)). ¹H NMR (400 MHz, d₆-DMSO) δ: 7.58 (m, 1H), 7.51 (d, 1H, J 3.3Hz), 7.30 (m, 1H), 7.15 (m, 1H), 7.05 (dd, 1H, J 8.3, 3.3 Hz), 6.84-6.73(m, 3H), 6.70 (d, 1H, J 8.3 Hz), 5.27 (dd, 1H, J 10.3, 2.3 Hz), 5.01 (s,2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.13 (m, 1H), 2.03 (m, 1H).

Example 71N-{6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]pyridin-3-yl}methaneSulfonamide

N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamide was prepared as described forN-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methane sulfonamide inExample 46 starting from 100 mg of6-[2-(2,4-difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example70). The product was crystallised from a mixture of methanol and diethylether. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.67 (s, 1H), 7.99 (d, 1H, J 2.8Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.60 (m, 1H), 7.30 (m, 1H), 7.16 (m,1H), 6.98 (d, 1H, J 8.8 Hz), 6.92-6.86 (m, 3H), 5.31 (dd, 1H, J 10.3,2.3 Hz), 3.01 (m, 1H), 2.98 (s, 3H), 2.76 (m, 1H), 2.16 (m, 1H), 2.06(m, 1H).

Example 72 2-(2,4-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(2,4-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) starting from 520 mg of2-(2,4-difluorophenyl)chroman-4,6-diol (Example 69(b)). The product wasrecrystallised from a mixture of 2-propanol and diethyl ether. 1H NMR(400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8Hz), 7.66 (m, 1H), 7.32 (m, 1H), 7.26 (d, 1H, J 2.9 Hz), 7.23 (d, 1H,9.1 Hz), 7.17 (m, 1H), 7.02 (dd, 1H, J 8.9, 2.9 Hz), 6.88 (d, 1H, J 8.9Hz), 5.70 (bs, 1H), 5.52 (dd, 1H, J 11.9, 1.5 Hz), 5.00 (m, 1H), 2.31(m, 1H), 2.09 (m, 1H).

Example 73 2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine a)2-(2-Chlorophenyl)-6-hydroxychroman-4-one

2-(2-Chlorophenyl)-6-hydroxychroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from3.0 g of 2 ′,5′-dihydroxyacetophenone and 2.8 g of 2-chlorobenzaldehyde.The product was passed though silica gel using heptane-ethyl acetate asan eluant and then triturated with ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ:9.49 (s, 1H), 7.77 (dd, 1H, J 7.7, 2.0 Hz), 7.53 (dd, 1H, J 7.6, 1.8Hz), 7.49-7.41 (m, 2H), 7.14 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9Hz), 6.93 (d, 1H, J 8.8 Hz), 5.78 (dd, 1H, J 13.6, 2.6 Hz), 3.19 (dd,1H, J −16.9, 13.6 Hz), 2.78 (dd, 1H, J −16.9, 2.6 Hz).

b) 2-(2-Chlorophenyl)chroman-4,6-diol

2-(2-Chlorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1.12 g of2(2-chlorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:7.63 (dd, 1H, J 7.7, 1.8 Hz), 7.49 (dd, 1H, J 7.8, 1.4 Hz), 7.45-7.36(m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.8 Hz), 6.56 (dd, 1H, J8.9, 2.9 Hz), 5.39 (dd, 1H, J 11.7, 1.5 Hz), 4.90 (m, 1H), 2.33 (m, 1H),1.82 (m, 1H).

c) 2-(2-Chlorophenyl)chroman-6-ol

2-(2-Chlorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of2-(2-chlorophenyl)-chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ:7.58-7.36 (m, 4H), 6.66 (m, 1H), 6.55-6.51 (m, 2H), 5.23 (dd, 1H, J10.1, 2.1 Hz), 2.92 (m, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.87 (m, 1H).

d) 2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 485 mg of 2-(2-chlorophenyl)chroman-6-ol. ¹H NMR (400MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.9, 0.5 Hz), 8.60 (dd, 1H, J 9.1, 2.9Hz), 7.62 (dd, 1H, J 7.5, 1.8 Hz), 7.51 (dd, 1H, J 7.6, 1.7 Hz),7.45-7.40 (m, 2H), 7.21 (dd, 1H, J 9.1, 0.5 Hz), 7.04 (d, 1H, J 2.7 Hz),6.99 (dd, 1H, J 8.8, 2.7 Hz), 6.94 (d, 1H, 8.8 Hz), 5.40 (dd, 1H, J10.4, 2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H), 2.24 (m, 1H), 1.95 (m, 1H).

Example 74 2-(2-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(2-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 520 mg of 2-(2-chlorophenyl)chroman-4,6-diol (Example68(b)). The product was recrystallised from 2-propanol. ¹H NMR (300 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.68(dd, 1H, J 7.6, 1.8 Hz), 7.51-7.40 (m, 3H), 7.27 (d, 1H, J 2.9 Hz), 7.23(d, 1H, J 9.1 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.92 (d, 1H, J 8.8 Hz),5.59 (d, 1H, J 10.6 Hz), 5.02 (m, 1H), 2.40 (m, 1H), 1.93 (m, 1H).

Example 75 5-Nitro-2-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridine a)6-Hydroxy-2-(4-fluorophenyl)chroman-4-one

6-Hydroxy-2-(4-fluorophenyl)chroman-4-one was prepared as described for2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from2.0 g of 2′,5′-dihydroxyacetophenone and 1.6 ml of 4-fluorobenzaldehyde.The product was recrystallised from acetic acid. ¹H NMR (400 MHz,d₆-DMSO) δ: 7.59 (m, 2H), 7.27 (m, 2H), 7.14 (d, 1H, J 3.1 Hz), 7.05(dd, 1H, J 8.9, 3.1 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.56 (dd, 1H, J 13.2,2.8 Hz), 3.18 (dd, 1H, J-16.9, 13.2 Hz), 2.77 (dd, 1H, J −16.9, 2.8 Hz).

b) 2-(4-Fluorophenyl)chroman-4,6-diol

2-(4-Fluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 1,5 g of2-(4-fluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.84 (s, 1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.89 (d, 1H, J 2.7 Hz), 6.59(d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.7 Hz), 5.42 (bs, 1H), 5.12 (d,1H, J 10.7 Hz), 4.87 (m, 1H), 2.25 (m, 1H), 1.89 (m, 1H).

c) 2-(4-Fluorophenyl)chroman-6-ol

2-(4-Fluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 480 mg of2-(4-fluorophenyl)-chroman-4,6-diol. ¹H NMR (400 MHz, CDCl₃) δ: 7.38 (m,2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6, 2.9 Hz),6.57 (d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2, 2.4 Hz), 2.95 (ddd, 1H, J−16.8, 11.4, 6.2 Hz), 2.74 (ddd, 1H, J −16.8, 5.3, 3.1 Hz), 2.15 (m,1H), 2.05 (m, 1H).

d) 2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 160 mg of 2-(4-fluorophenyl)chroman-6-ol. The productwas purified on preparative TLC-plate covered with silica gel usingheptane-ethyl acetate (4:1) as an eluant. ¹H NMR (400 MHz, d₆-DMSO) δ:9.04 (dd, 1H, J 2.9, 0.4 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.51 (m,2H), 7.24 (m, 1H), 7.20 (dd, 1H, J 9.1, 0.4 Hz), 7.01 (d, 1H, J 2.8 Hz),6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.91 (d, 1H, 8.7 Hz), 5.15 (dd, 1H, J10.3, 2.2 Hz), 2.94 (m, 1H), 2.76 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).

Example 76 6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine

6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26starting from 3.04 g of2-[2-(4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 75(d)).¹H NMR (400 MHz, d₆-DMSO) δ: 7.52-7.47 (m, 3H), 7.24 (m, 2H), 7.05 (dd,1H, J 8.6, 3.0 Hz), 6.84-6.68 (m, 4H), 5.09 (dd, 1H, J 10.2, 2.1 Hz),5.00 (bs, 2H), 2.93 (m, 1H), 2.69 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H).

Example 77 N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methaneSulfonamide

N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamidewas prepared as described forN-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methane sulfonamide inExample 46 starting from 442 mg of6-[2-(4-fluorophenyl)-chroman-6-yloxy]-pyridin-3-ylamine (Example 76).The product was passed through silica gel using ethyl acetate-heptane(10:3) as an eluant and then crystallised from diethyl ether. ¹H NMR(400 MHz, CDCl₃) δ: 8.09 (d, 1H, J 2.8 Hz), 7.72 (dd, 1H, J 8.9, 2.8Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, 1H), 5.03(dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 3.00 (s, 3H), 2.80 (m, 1H), 2.19(m, 1H), 2.07 (m, 1H).

Example 78 2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]5-nitropyridine a)2-(2,3-Difluorophenyl)-6-hydroxychroman-4-one

2-(2,3-Difluorophenyl)-6-hydroxychroman-4-one was prepared as describedfor 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) startingfrom 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of2,3-difluorobenzaldehyde. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.51 (s, 1H),7.53-7.46 (m, 2H), 7.31 (m, 1H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, 38.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.82 (dd, 1H, J 13.4, 2.8 Hz),3.26 (dd, 1H, J −16.9, 13.4 Hz), 2.79 (dd, 1H, J −16.9, 2.8 Hz).

b) 2-(2,3-Difluorophenyl)chroman-4,6-diol

2-(2,3-Difluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 2.91 g of2-(2,3-difluorophenyl)-6-hydroxychroman-4-one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.88 (s, 1H), 7.45-7.36 (m, 2H), 7.28 (m, 1H), 6.89 (d, 1H, J 2.8Hz), 6.61 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49 (bs,1H), 5.40 (dd, 1H, J 11.8, 1.4 Hz), 4.90 (m, 1H), 2.28 (m, 1H), 1.99 (m,1H).

c) 2-(2,3-Difluorophenyl)chroman-6-ol

2-(2,3-Difluorophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 1.5 g of2-(2,3-difluorophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ:8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 6.64 (dd, 1H,9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2, 2.2 Hz), 2.93 (m,1H), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).

d) 2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 1.88 g of 2-(2,3-difluorophenyl)chroman-6-ol. ¹H NMR(400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1, 3.0Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, 9.1 Hz),7.03 (d, 1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.92 (d, 1H, 8.8Hz), 5.42 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m,1H), 2.08 (m, 1H).

Example 79 2-(2,6-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ola) 6-Hydroxy-2-(2,6-difluorophenyl)chroman-4-one

6-Hydroxy-2-(2,6-Difluorophenyl)chroman-4-one was prepared as describedfor 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) startingfrom 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of2,6-difluorobenzaldehyde. The product was triturated from ethanol. ¹HNMR (400 MHz, d₆-DMSO) δ: 7.55 (m, 1H) 7.22-7.18 (m, 2H), 7.14 (d, 1H, J3.0 Hz), 7.03 (dd, 1H, J 8.9, 3.0 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.84 (dd,1H, J 14.0, 3.0 Hz), 3.38 (dd, 1H, J −17.0, 14.0 Hz), 2.80 (dd, 1H, J−17.0, 3.0 Hz).

b) 2-(2,6-Difluorophenyl)chroman-4,6-diol

2-(2,6-Difluorophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from 4.45 g of2-(2,6-difluorophenyl)-6-hydroxychroman-4one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.87 (s, 1H), 7.48 (m, 1H), 7.17-7.13 (m, 2H), 6.90 (d, 1H, J 2.9Hz), 6.55-6.54 (m, 2H), 5.46 (dd, 1H, J 12.2, 1.8 Hz), 4.87 (m, 1H),2.37 (m, 1H), 2.23 (m, 1H).

c) 2-(2,6-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(2,6-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) starting from 1.9 g of2-(2,6-difluorophenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ:9.03 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.52 (m, 1H),7.26-7.16 (m, 4H), 7.01 (dd, 1H, J 8.8, 2.9 Hz), 6.83 (d, 1H, 8.8 Hz),5.69-5.64 (m, 2H), 4.98 (m, 1H), 2.37 (m, 1H), 2.29 (m, 1H).

Example 806-(5-Nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol a)6-Hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one

6-Hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one was prepared asdescribed for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a)starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 3.0 ml of2-trifluoromethylbenzaldehyde. The product was triturated from ethanol.¹H NMR (300 MHz, d₆-DMSO) δ: 9.48 (s, 1H), 8.07 (m, 1H), 7.86-7.79 (m,2H), 7.66 (m, 1H), 7.15 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz),6.95 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 13.8, 2.4 Hz), 3.38 (dd, 1H, J−16.9, 13.8 Hz), 2.66 (dd, 1H, J −16.9, 3.0 Hz).

b) 2-(2-Trifluoromethylphenyl)chroman-4,6-diol

2-(2-Trifluoromethylophenyl)chroman-4,6-diol was prepared as describedfor 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.43 g of2-(2-trifluoromethylphenyl)-6-hydroxychroman-4-one. ¹H NMR (300 MHz,d₆-DMSO) δ: 8.89 (s, 1H), 7.83 (m, 1H), 7.79-7.74 (m, 2H), 7.58 (m, 1H),6.90 (d, 1H, J 2.7 Hz), 6.61 (d, 1H, J 8.9 Hz), 6.56 (dd, 1H, J 8.7, 2.7Hz), 5.51 (d, 1H, J 6.5 Hz), 5.34 (d, 1H, J 11.6 Hz), 4.88 (m, 1H), 2.21(m, 1H), 1.95 (m, 1H).

c) 6-(5-Nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol

6-(5-Nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) starting from 350 mg of2-(2-trifluoromethylphenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO)δ: 9.04 (d, 1H, J 2.8 Hz), 8.62 (dd, 1H, J 9.1, 2.8 Hz), 7.89 (m, 1H),7.82-7.78 (m, 2H), 7.62 (m, 1H), 7.28 (d, 1H, J 2.7 Hz), 7.24 (d, 1H,9.1 Hz), 7.04 (dd, 1H, J 8.7, 2.7 Hz), 6.90 (d, 1H, J 8.7 Hz), 5.7 (bs,1H), 5.38 (d, 1H, J 11.6 Hz), 5.01 (m, 1H), 2.29 (m, 1H), 2.05 (m, 1H).

Example 81 2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine a)2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone

(3-Fluorophenyl)acetic acid (3.7 g) and 3-methoxyphenol (3.0 g) weredissolved into BF₃Et₂O (60 ml, 20 eq) under argon. The mixture wasstirred at 60-70° C. until disappearance of the starting materials (9 h)and poured into large volume of ice water. After extraction with ethylacetate the combined organic layers were washed with water, dried andevaporated. The crude product was purified by column chromatographyusing CH₂Cl₂ as an eluant. ¹H NMR (400 MHz, d₆-DMSO) δ: 12.41 (br s,1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.38 (m, 1H), 7.09-7.13 (m, 3H), 6.56(dd, 1H, J 9.0, 2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s,3H).

b) 3-(3-Fluorophenyl)-7-methoxychromen-4-one

2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone (1.76 g) wasdissolved in pyridine (88 ml). Piperidine (8.8 ml) andtriethylorthoformate (88 ml) were added and the mixture was stirred at120° C. for 3.5 hours. After pouring the mixture into water andacidification with conc. HCl the crude product was filtered.Purification by column chromatography using heptane-ethyl acetate (7:3)as an eluant afforded 3-(3-fluorophenyl)-7-methoxychromen-4-one. ¹H NMR(400 MHz, d₆-DMSO) δ: 8.57 (s, 1H), 8.06 (d, 1H, J 8.9 Hz), 7.45-7.50(m, 3H), 7.21-7.25 (m, 1H), 7.20 (d, 1H, J 2.4 Hz), 7.12 (dd, 1H, J 8.9,2.4 Hz), 3.92 (s, 3H).

c) 3-(3-Fluorophenyl)-7-hydroxychromen-4-one

3-(3-Fluorophenyl)-7-methoxychromen-4one (320 mg) was refluxed with 47%HBr (18 ml) until disappearance of the starting material. The mixturewas poured into water and the precipitate was filtrated and driedyielding 3-(3-fluorophenyl)-7-hydroxychromen-4-one. ¹H NMR (400 MHz,d₆-DMSO) δ: 10.87 (s, 1H), 8.49 (s, 1H), 7.99 (d, 1H, J 8.7 Hz),7.43-7.49 (m, 3H), 7.20-7.24 (m, 1H), 6.97 (dd, 1H, J 8.7, 2.2 Hz), 6.90(d, 1H, J 2.2 Hz).

d) 3-(3-Fluorophenyl)chroman-7-ol

3-(3-Fluorophenyl)-7-hydroxychromen-4-one (160 mg) was dissolved inethanol (40 ml) and 10% palladium on carbon (400 mg) was added. Thereaction mixture was hydrogenated for 6 hours at normal pressure androom temperature. It was then filtered through Celite and washed withethanol. The solvent was evaporated under reduced pressure to give3-(3-fluorophenyl)chroman-7-ol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.19 (br s,1H), 7.38 (m, 1H), 7.17-7.21 (m, 2H), 7.08 (m, 1H), 6.88 (d, 1H, J 8.2Hz), 6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.22 (dd, 1H,J 10.3, 3.6 Hz), 4.02 (t, 1H, 10.3 Hz), 3.20 (m, 1H), 2.90 (m, 2H).

e) 2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine

2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) using 125 mg of 3-(3-fluorophenyl)-chroman-7-ol. The product wasrecrystallised from ethanol. ¹H NMR (400 MHz, CDCl₃) δ: 9.07 (d, 1H, J2.8 Hz), 8.47 (dd, 1H, J 9.0, 2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H, J 8.9Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, 1H, J 10.6, 4.3Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).

Example 82 5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine a)7-Hydroxy-3-phenylchromen-4-one

7-Hydroxy-3-phenylchromen-4-one is commercially available or can besynthesised by methods described for3-(3-fluorophenyl)-7-hydroxychromen-4-one (Example 81(a-c)). ¹H NMRspectrum as reported in the literature (Synth. Commun., 2000, 30(3),469-484).

b) 3-Phenylchroman-7-ol

3-Phenylchroman-7-ol was prepared as described for3-(3-fluorophenyl)-chroman-7-ol in Example 81(d) using 0.5 g of7-hydroxy-3-phenylchromen-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.18 (brs, 1H), 7.31-7.34 (m, 4H), 7.25-7.27 (m, 1H), 6.88 (d, 1H, J 8.2 Hz),6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.21 (dd, 1H, J10.3, 3.6 Hz), 4.00 (t, 1H, 10.3 Hz), 3.13 (m, 1H), 2.84-2.87 (m, 2H).

c) 5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine

5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine was prepared as describedfor 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using200 mg of 3-phenylchroman-7-ol. ¹H NMR (400 MHz, d₆-DMSO) δ: δ: 9.05 (d,1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.34-7.38 (m, 4H),7.27-7.30 (m, 1H), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31 (dd, 1H, J10.4, 3.5 Hz), 4.12 (t, 1H, 10.4 Hz), 3.24 (m, 1H), 3.01-3.11 (m, 2H).

Example 83 5-Methoxy-2-(3-phenylchroman-7-yloxy)phenylamineHydrochloride a) 7-(4-Methoxy-2-nitrophenoxy)-3-phenylchroman

7-(4-Methoxy-2-nitrophenoxy)-3-phenylchroman was prepared as describedfor 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using0.5 g of 3-phenylchroman-7-ol. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.60 (d, 1H,J 3.1 Hz), 7.35 (m, 4H), 7.32 (dd, 1H, J 9.1, 3.1 Hz), 7.27-7.29 (m,1H), 7.21 (d, 1H, J 9.1 Hz), 7.12 (d, 1H, J 8.3 Hz), 6.48 (dd, 1H, J8.3, 2.5 Hz), 6.38 (d, 1H, J 2.5 Hz), 4.26 (dd, 1H, J 10.4, 3.5 Hz),4.08 (t, 1H, J 10.4 Hz), 3.85 (s, 3H), 3.20 (m, 1H), 2.90-3.04 (m, 2H).

b) 5-Methoxy-2-(3-phenylchroman-7-yloxy)phenylamine Hydrochloride

5-Methoxy-2-(3-phenylchroman-7-yloxy)phenylamine hydrochloride wasprepared as described for5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride inExample 3(b) using 310 mg of7-(4-methoxy-2-nitrophenoxy)-3-phenylchroman. ¹H NMR (400 MHz, d₆-DMSO)δ: 7.32-7.35 (m, 4H), 7.23-7.29 (m, 1H), 7.05 (d, 1H, J 8.4 Hz), 6.76(d, 1H, J 8.8. Hz), 6.46 (d, 1H, J 2.8 Hz), 6.43 (dd, 1H, J 8.4, 2.5Hz), 6.28 (d, 1H, J 2.5 Hz), 6.24 (dd, 1H, J 8.8, 2.8 Hz), 4.24 (dd, 1H,J 10.4, 3.4 Hz), 4.05 (t, 1H, J 10.4 Hz), 3.18 (m, 1H), 2.88-3.01 (m,2H).

Example 845-Nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine a)2-(2-Hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol

To a stirred solution of 2-mercaptobenzene-1,4-diol (0.5 g) andpotassium carbonate (0.49 g) in water (5 ml) was added 2-phenyloxirane(0.40 ml) under argon. The mixture was stirred at room temperature for2.5 hours and then treated with 2 M HCl and extracted with ethylacetate. The combined organic layers were washed with water and brine,dried and evaporated. The crude product was purified by columnchromatography using heptane-ethyl acetate (1:1) as an eluant. ¹H NMR(400 MHz, d₆-DMSO) δ: 8.94 (br s, 1H), 8.72 (br s, 1H), 7.24-7.37 (m,5H), 6.62-6.65 (m, 2H), 6.47 (dd, 1H, J 8.6, 2.8 Hz), 4.97 (br s, 1H),4.34 (m, 1H), 3.72 (m, 2H).

b) 2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol

A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol (0.83g) in dry toluene (60 ml) was stirred with Amberlyst 15 (0.5 g) at 60°C. until disappearance of the starting material. After the mixture wasfiltered and solvent evaporated the crude product was purified by columnchromatography using heptane-ethyl acetate (1:1) as an eluant. ¹H NMR(400 MHz, CDCl₃) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7, 3.0 Hz), 5.10 (dd, 1H,J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0, 9.6 Hz), 3.06 (dd, 1H, J 13.0, 1.9Hz).

c) 5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine

5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine wasprepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine inExample 1(b) using 269 mg 2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol.The product was recrystallised from ethanol. ¹H NMR (400 MHz, CDCl₃) δ:9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.43 (m, 4H),7.37-7.41 (m, 1H), 7.02 (d, 1H, J 9.1 Hz), 6.99 (d, 1H, J 8.9 Hz), 6.95(d, 1H, J 2.8 Hz), 6.82 (dd, 1H, J 8.9, 2.8 Hz), 5.21 (dd, 1H, J 9.7,1.9 Hz), 3.31 (dd, 1H, 13.2, 9.7 Hz), 3.11 (dd, 1H, 13.2, 1.9 Hz).

Example 855-Nitro-2-(4-oxo-2-phenyl-3,4-dihydrobenzo[1.4]oxathiin-6-yloxy)pyridine

To 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine(214 mg) in methanol (80 ml) at 60° C., NaIO₄ (total 2.5 eq) was addedin small portions until disappearance of the starting material. Themixture was poured into water and precipitate was filtered and washedwith water. The crude product was purified by column chromatographyusing heptane-ethyl acetate (1:1) as an eluant. ¹H NMR (400 MHz, CDCl₃)δ: 9.02 (d, 1H, J 2.8 Hz), 8.51 (dd, 1H, J 9.1, 2.8 Hz), 7.45-7.56 (m,6H), 7.32 (dd, 1H, J 9.0, 2.8 Hz), 7.21 (d, 1H, J 9.0 Hz), 7.10 (d, 1H,J 9.1 Hz), 5.77 (dd, 1H, J 12.0, 1.5 Hz), 3.34 (dd, 1H, 14.4, 1.5 Hz),3.13 (dd, 1H, 14.4, 12.0 Hz).

Example 862-(4,4-Dioxo-2-phenyl-3,4-dihydro-2-benzo[1,4]oxathiin-6-yloxy)-5-nitropyridine

To stirred solution of5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine (150mg) in AcOH (3.7 ml) and water (1.2 ml) was added KMnO₄ (125 mg) in anice/water bath. The mixture was stirred at room temperature for 1.5hours, then water (5 ml) and 30% H₂O₂ were added until decomposition ofexcess KMnO₄ was complete. The mixture was diluted with additional water(20 ml). The white precipitate was filtered, washed with water and driedto give2-(4,4-dioxo-2-phenyl-3,4-dihydro-2-benzo[1,4]oxathiin-6-yloxy)-5-nitropyridine.¹H NMR (400 MHz, CDCl₃) δ: 9.03 (d, 1H, J 2.8 Hz), 8.52 (dd, 1H, J 9.0,2.8 Hz), 7.68 (d, 1H, J 2.8 Hz), 7.46-7.52 (m, 5H), 7.33 (dd, 1H, J 9.1,2.8 Hz), 7.17 (d, 1H, J 9.1 Hz), 7.11 (d, 1H, J 9.0 Hz), 5.87 (dd, 1H, J12.2, 1.6 Hz), 3.76 (dd, 1H, 14.1, 12.2 Hz), 3.55 (dd, 1H, 14.1, 1.6Hz).

Example 87 5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine a)6-Hydroxy-2-(4-nitrophenyl)chroman-4-one

6-Hydroxy-2-(4-nitrophenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.48 (s,1H), 8.29 (d, 2H, J 6.9 Hz), 7.83 (d, 2H, J 6.9 Hz), 7.13 (d, 1H J 2.9Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 7.01 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H,J 13.0, 3.0 Hz), 3.15 (dd, 1H, J 16.8, 13.0 Hz), 2.89 (dd, 1H, J 16.8,3.0 Hz).

b) 2-(4-Nitrophenyl)chroman-4,6-diol

2-(4-Nitrophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) staring from6-hydroxy-2-(4-nitrophenyl)-chroman-4-one. ¹H NMR (300 MHz, d₆-DMSO) δ:8.86 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.74 (d, 2H, J 6.9 Hz), 6.89 (d,1H J 2.8 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.56 (dd, 1H, J 8.6, 2.8 Hz), 5.46(d, 1H, J 6.9 Hz), 5.32 (d, 1H, J 10.5 Hz), 4.86-4.94 (m, 1H), 2.31-2.38(m, 1H), 1.78-1.89 (m, 1H).

c) 2-(4-Nitrophenyl)chroman-6-ol

2-(4-Nitrophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from2-(4-nitrophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.84 (s,1H), 8.26 (d, 2H, J 6.9 Hz), 7.71 (d, 2H, J 6.9 Hz), 6.69 (d, 1H, J 8.6Hz), 6.53 (dd, 1H, J 8.6, 2.8 Hz), 6.50 (d, 1H, J 2.8 Hz), 5.19 (dd, 1H,J 9.9, 2.2 Hz), 2.87-2.91 (m, 1H), 2.61-2.66 (m, 1H), 2.16-2.21 (m, 1H),1.89-1.93 (m, 1H).

d) 5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine

5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(4-nitrophenyl)chroman-6-ol. ¹H NMR (300 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.29(d, 2H, J 6.9 Hz), 7.76 (d, 2H, J 6.9 Hz), 7.21 (d, 1H, J 9.1 Hz),6.98-7.02 (m, 3H), 5.35 (dd, 1H, J 9.9, 2.2 Hz), 2.96-3.05 (m, 1H),2.73-2.78 (m, 1H), 2.24-2.29 (m, 1H), 1.96-2.04 (m, 1H).

Example 88 6-[2-(4-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(4-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26using 100 mg 5-nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine(Example 87(d)) and 665 mg of Zn. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.50 (d,1H, J 2.9 Hz), 7.07 (d, 2H, 8.4 Hz), 7.04 (dd, 1H, J 8.6, 2.9 Hz), 6.71(s, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.56 (d, 2H, J 8.4 Hz), 5.07 (s, 2H),4.99 (s, 2H), 4.84 (dd, 1H, J 9.7, 2.3 Hz), 2.86-2.95 (m, 1H), 2.66-2.71(m, 1H), 1.95-2.05 (m, 2H).

Example 89 5-Nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine a)6-Hydroxy-2-(2-nitrophenyl)chroman-4-one

6-Hydroxy-2-(2-nitrophenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). ¹H NMR (400MHz, d₆-DMSO) δ: 9.49 (s, 1H), 8.05-8.06 (m, 1H), 7.96-7.98 (m, 1H),7.83-7.87 (m, 1H), 7.65-7.69 (m, 1H), 7.14 (d, 1H, J 3.1 Hz), 7.05 (dd,1H, J 8.8, 3.1 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.69 (dd, 1H, J 13.0, 2.6Hz), 3.22 (dd, 1H, J 16.8, 13.0 Hz), 2.98 (dd, 1H, J 16.8, 2.6 Hz).

b) 2-(2-Nitrophenyl)chroman-4,6-diol

2-(2-Nitrophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(2-nitrophenyl)-chroman-4-one. ¹H NMR (300 MHz, d₆-DMSO) δ:8.87 (s, 1H), 7.99-8.02 (m, 1H), 7.77-7.86 (m, 2H), 7.59-7.64 (m, 1H),6.89 (d, 1H, J 2.4 Hz), 6.56-6.57 (m, 2H), 5.51-5.55 (m, 2H), 4.85-4.92(m, 1H), 2.42-2.47 (m, 1H), 1.85-1.96 (m, 1H).

c) 2-(2-Nitrophenyl)chroman-6-ol

2-(2-Nitrophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from2-(2-nitrophenyl)chroman-4,6-diol. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.85 (s,1H), 8.00 (d, 1H, J 8.0 Hz), 7.79-7.80 (m, 2H), 7.59-7.63 (m, 1H),6.59-6.62 (m, 1H), 6.50-6.53 (m, 2H), 5.36 (dd, 1H, J 10.2, 2.0 Hz),2.89-2.93 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.31 (m, 1H), 1.90-1.95 (m,1H).

d) 5-Nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine

5-Nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(2-nitrophenyl)chroman-6-ol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.03(d, 1H, J 7.9 Hz), 7.80-7.85 (m, 2H), 7.62-7.66 (m, 1H), 7.22 (d, 1H, J9.1 Hz), 7.04 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.8, 2.8 Hz), 6.88 (d,1H, J 8.8 Hz), 5.52 (dd, 1H, J 10.3, 2.0 Hz), 2.99-3.31 (m, 1H),2.80-2.85 (m, 1H), 2.35-2.40 (m, 1H), 1.99-2.04 (m, 1H).

Example 90 6-[2-(2Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(2-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26using 100 mg 5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine(Example 89(d)) and 700 mg of Zn. ¹H NMR (300 MHz, d₆-DMSO) δ: 7.51 (d,1H, J 2.9 Hz), 7.15-7.18 (m, 1H), 7.05 (dd, 1H, J 8.6, 2.9 Hz),6.98-7.00 (m, 1H), 6.77 (d, 1H, J 8.6 Hz), 6.73-6.75 (m, 2H), 6.66-6.71(m, 2H), 6.56-6.61 (m, 1H), 5.11 (dd, 1H, J 10.4, 2.0 Hz), 5.01 (s, 2H),4.99 (s, 2H), 2.94-2.99 (m, 1H), 2.66-2.74 (m, 1H), 2.06-2.13 (m, 1H),1.88-1.95 (m, 1H).

Example 91N-{6-[2-(2-Acetylaminophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(2-Acetylaminophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide wasprepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 6-[2-(2-aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine(Example 90). ¹H NMR (300 MHz, d₆-DMSO) δ: 10.02 (s, 1H), 9.44 (s, 1H),8.27 (d, 1H, J 2.7 Hz), 8.00 (dd, 1H, J 8.8, 2.7 Hz), 7.49 (d, 1H, J 8.8Hz), 7.25-7.38 (m, 3H), 6.92 (d, 1H, J 8.9 Hz), 6.88 (s, 1H), 6.83 (s,2H), 5.22 (d, 1H, J 8.7 Hz), 2.90-2.99 (m, 1H), 2.72-2.79 (m, 1H),2.12-2.18 (m, 1H), 2.04 (s, 6H), 1.86-1.94 (m, 1H).

Example 92 5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine a)6-Hydroxy-2-(3-nitrophenyl)chroman-4-one

6-Hydroxy-2-(3-nitrophenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (300 MHz, d₆-DMSO) δ: 8.40 (s,1H), 8.24 (dd, 1H, J 8.2, 2.3 Hz), 8.01 (d, 1H, J 7.9 Hz), 7.74 (t, 1H,J 15.9, 7.9 Hz), 7.13 (d, 1H, J 2.9 Hz), 7.07 (dd, 1H, J 8.8, 2.9 Hz),7.00 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 13.1, 2.9 Hz), 3.21 (dd, 1H, J16.8, 13.1 Hz), 2.88 (dd, 1H, J 16.8, 2.9 Hz).

b) 2-(3-Nitrophenyl)chroman-4,6-diol

2-(3-Nitrophenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(3-nitrophenyl)chroman-4-one. ¹H NMR (400 MHz, d₆-DMSO) δ:8.89 (br s, 1H), 8.29 (s, 1H), 8.20 (dd, 1H, J 8.2, 2.3Hz), 7.93(d, 1H,J 7.9Hz), 7.71 (t, 1H, J 15.9, 7.9Hz), 6.89 (d, 1H, J 2.8 Hz), 6.66 (d,1H, J 8.7 Hz), 6.57 (dd, 1H, J 8.7, 2.9 Hz), 5.47 (br s, 1H), 5.33 (d,1H, J 10.7 Hz), 4.88-4.92 (m, 1H), 2.33-2.39 (m, 1H), 1.83-1.92 (m, 1H).

c) 2-(3-Nitrophenyl)chroman-6-ol

2-3-Nitrophenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from2-(3-nitrophenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ: 8.80 (s,1H), 8.26 (s, 1H), 8.19 (dd, 1H, J 8.1, 2.3 Hz), 7.90 (d, 1H, J 7.9Hz),7.70 (t, 1H, J 15.9, 7.9 Hz), 6.70 (d, 1H, J 8.4 Hz), 6.51-6.55 (m, 2H),5.19 (dd, 1H, J 10.0, 2.0), 2.86-2.91 (m, 1H), 2.61-2.68 (m, 1H),2.17-2.23 (m, 1H), 1.91-1.97 (m, 1H).

d) 5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine

5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(3-nitrophenyl)chroman-6-ol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 8.32(s, 1H), 8.23 (d, 1H, J 8.3 Hz), 7.95 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J15.8, 7.9 Hz), 7.21 (d, 1H, J 9.0 Hz), 6.96-7.03 (m, 3H), 5.35 (d, 1H, J8.7 Hz), 2.98-3.06 (m, 1H), 2.72-2.79 (m, 1H), 2.26-2.33 (m, 1H),1.99-2.06 (m, 1H).

Example 93 6-[2-(3-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine

6-[2-(3-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26using 150 mg 5-nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine(Example 92(d)) and 997 mg of Zn. ¹H NMR (300 MHz, d₆-DMSO) δ: 7.51 (d,1H, J 2.8 Hz), 7.05 (dd, 1H, J 8.6, 2.8 Hz), 7.01 (t, 1H, J 15.4, 7.7Hz), 6.70-6.78 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.63 (s, 1H), 6.54 (d,1H, J 7.7 Hz), 6.50 (d, 1H, J 8.6 Hz), 5.06 (s, 2H), 4.98 (s, 2H), 4.90(dd, 1H, J 10.0, 2.2 Hz), 2.85-2.96 (m, 1H), 2.62-2.74 (m, 1H),2.05-2.11 (m, 1H), 1.89-1.95 (m, 1H).

Example 94 2-(4-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol a)6-Hydroxy-2-(4-methoxyphenyl)chroman-4-one

6-Hydroxy-2-(4-methoxyphenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.40 (s,1H), 7.45 (d, 2H, J 8.7 Hz), 7.11 (d, 1H, J 3.0 Hz), 7.02 (dd, 1H, J8.9, 3.0 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.47 (dd,1H, J 13.1, 2.8 Hz), 3.77 (s, 3H), 3.19 (dd, 1H, J 16.8, 13.1 Hz), 2.72(dd, 1H, J 16.8, 2.8 Hz).

b) 2-(4-methoxyphenyl)chroman-4,6-diol

2-(4-Methoxyphenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(4-methoxyphenyl)chroman-4-one. ¹H NMR (300 MHz, d₆-DMSO) δ:8.78 (s, 1H), 7.35 (d, 2H, J 8.7 Hz), 6.94 (d, 2H, J 8.7 Hz), 6.88 (d,1H, J 2.5 Hz), 6.56 (d, 1H, J 8.7 Hz), 6.52 (dd, 1H, J 8.7, 2.5 Hz),5.37 (br s, 1H), 5.04 (d, 1H, J 10.9 Hz), 4.83-4.89 (m, 1H), 3.76 (s,3H), 2.18-2.25 (m, 1H), 1.85-1.97 (m, 1H).

c) 2-(4-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(4-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(4-methoxyphenyl)chroman-4,6-diol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.40(d, 2H, J 8.7 Hz), 7.24 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.00(dd, 1H, J 8.7, 2.8 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.84 (d, 1H, J 8.7 Hz),5.63 (d, 1H, J 6.4 Hz), 5.23 (d, 1H, J 10.8 Hz), 4.95-5.02 (m, 1H), 3.78(s, 3H), 2.25-2.29 (m, 1H), 1.98-2.04 (m, 1H).

Example 95 6-(5-Aminopyridin-2-yloxy-2-(4-methoxyphenyl)chroman-4-ol

6-(5-Aminopyridin-2-yloxy)-2-(4-methoxyphenyl)chroman-4-ol was preparedas described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example26 using 105 mg2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example94(c)) and 348 mg of Zn. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.52 (d, 1H, J 3.0Hz), 7.38 (d, 2H, J 8.8 Hz), 7.06 (dd, 1H, J 8.7, 3.0 Hz), 7.04 (d, 1H,J 2.9 Hz), 6.96 (d, 2H, J 8.8 Hz), 6.77 (dd, 1H, J 8.7, 2.9 Hz), 6.72(d, 1H, J 8.7 Hz), 6.70 (d, 1H, J 8.6 Hz), 5.52 (d, 1H, J 6.6 Hz), 5.15(d, 1H, J 10.7 Hz), 5.01 (s, 2H), 4.87-4.93 (m, 1H), 3.77 (s, 3H),2.22-2.26 (m, 1H), 1.90-1.99 (m, 1H).

Example 96N-{6-[4-Hydroxy-2-(4-methoxyphenyl)chroman-6-yloxy]pyridin-3-yl}Acetamide

N-{6-[4-Hydroxy-2-(4-methoxyphenyl)chroman-6-yloxy]pyridin-3-yl}-acetamidewas prepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 6-(5-aminopyridin-2-yloxy)-2-(4-methoxyphenyl)chroman-4-ol(Example 95). ¹H NMR (400 MHz, d₆-DMSO) δ: 10.05 (s, 1H), 8.28 (d, 1H, J2.7 Hz), 8.01 (dd, 1H, J 8.8, 2.7 Hz), 7.39 (d, 2H, J 8.7 Hz), 7.14 (d,1H, J 2.7 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.94 (d, 1H, J 8.8 Hz), 6.88 (dd,1H, J 8.8, 2.7 Hz), 6.77 (d, 1H, J 8.8 Hz), 5.57 (d, 1H, J 6.5 Hz), 5.19(d, 1H, J 10.6 Hz), 4.90-4.97 (m, 1H), 3.77 (s, 3H), 2.24-2.27 (m, 1H),2.04 (s, 3H), 1.93-2.01 (m, 1H).

Example 97 2-(2-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol a)6-Hydroxy-2-(2-methoxyphenyl)chroman-4-one

6-Hydroxy-2-(2-methoxyphenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.40 (s,1H), 7.56 (dd, 1H, J 7.6, 1.6 Hz), 7.37 (dt, 1H, J 8.6, 7.0, 1.6 Hz),7.12 (d, 1H, J 2.9 Hz), 7.07 (d, 1H, J 8.6 Hz), 7.03 (d, 1H, J 8.9 Hz),7.02 (d, 1H, J 7.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 5.70 (dd, 1H, J 13.3,2.7 Hz), 3.82 (s, 3H), 3.09 (dd, 1H, J 16.8, 13.3 Hz), 2.71 (dd, 1H, J16.8, 2.7 Hz).

b) 2-(2-methoxyphenyl)chroman-4,6-diol

2-(2-Methoxyphenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(2-methoxyphenyl)-chroman-4-one. ¹H NMR (300 MHz, d₆-DMSO)δ: 8.79 (s, 1H), 7.45 (dd, 1H, J 7.6, 1.6 Hz), 7.31 (dt, 1H, J 8.5, 7.3,1.6 Hz), 7.04 (d, 1H, J 8.5 Hz), 6.99 (d, 1H, J 7.3 Hz), 6.88 (d, 1H, J2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.7 Hz), 5.38 (s,1H), 5.34 (d, 1H, J 11.4 Hz), 4.80-4.88 (m, 1H), 3.81 (s, 3H), 2.24-2.28(m, 1H), 1.74-1.86 (m, 1H).

c) 2-(2-Methoxyphenyl)-6-5-nitropyridin-2-yloxy)chroman-4-ol

2-(2-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(2-methoxyphenyl)chroman-4,6-diol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.49(dd, 1H, J 7.6, 1.7 Hz), 7.34 (dt, 1H, J 8.3, 7.5, 1.7 Hz), 7.24 (d, 1H,J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.07 (d, 1H, J 8.3 Hz), 7.03 (d, 1H,J 7.5 Hz), 7.01 (dd, 1H, J 8.7, 2.8 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.62(d, 1H, J 6.3 Hz), 5.52 (d, 1H, J 10.4 Hz), 4.93-4.99 (m, 1H), 3.84 (s,3H), 2.30-2.35 (m, 1H), 1.85-1.94 (m, 1H).

Example 98 6-(5-Aminopyridin-2-yloxy)-2-(2-methoxyphenyl)chroman-4-ol

6-(5-Aminopyridin-2-yloxy)-2-(2-methoxyphenyl)chroman-4-ol was preparedas described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example26 using 79 mg2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example97(c)) and 262 mg of Zn. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.52 (d, 1H, J 2.9Hz), 7.47 (dd, 1H, J 7.5, 1.6 Hz), 7.33 (dt, 1H, J 8.5, 7.4, 1.6 Hz),7.06 (d, 1H, J 2.8 Hz), 7.03-7.05 (m, 2H), 7.01 (d, 1H, J 7.4 Hz), 6.79(dd, 1H, J 8.6, 2.8 Hz), 6.75 (d, 1H, J 8.7 Hz), 6.71 (d, 1H, J 8.6 Hz),5.52 (d, 1H, J 6.5 Hz), 5.44 (d, 1H, J 10.5 Hz), 5.01 (s, 2H), 4.86-4.92(m, 1H), 3.83 (s, 3H), 2.27-2.32 (m, 1H), 1.80-1.88 (m, 1H).

Example 99 2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine a)6-Hydroxy-2-(3-methoxyphenyl)chroman-4-one

6-Hydroxy-2-(3-methoxyphenyl)chroman-4-one was prepared as described for6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The productwas recrystallised from ethanol. ¹H NMR (400 MHz, d₆-DMSO) δ: 9.42 (s,1H), 7.33 (t, 1H, J 15.8, 8.3 Hz), 7.12 (d, 1H, J 3.0 Hz), 7.10 (s, 1H),7.09 (d, 1H, J 8.3 Hz), 7.04 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, 8.8Hz), 6.93 (dd, 1H, J 8.0, 2.5 Hz), 5.52 (dd, 1H, J 12.9, 2.9 Hz), 3.77(s, 3H), 3.17 (dd, 1H, J 16.9, 12.9 Hz), 2.77 (dd, 1H, J 16.9, 2.9 Hz).

b) 2-(3-methoxyphenyl)chroman-4,6-diol

2-(3-Methoxyphenyl)chroman-4,6-diol was prepared as described for2-phenylchroman-4,6-diol in Example 8(a) starting from6-hydroxy-2-(3-methoxyphenyl)-chroman-4-one. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.82 (s, 1H), 7.31 (t, 1H, J 15.7, 7.9 Hz), 6.99-7.02 (m, 2H),6.88-6.90 (m, 2H), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz),5.40 (d, 1H, J 7.0 Hz), 5.08 (d, 1H, J 11.5 Hz), 4.83-4.89 (m, 1H), 3.77(s, 3H), 2.23-2.28 (m, 1H), 1.83-1.92 (m, 1H).

c) 2-(3-Methoxyphenyl)chroman-6-ol

2-(3-Methoxyphenyl)chroman-6-ol was prepared as described for2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from2-(3-methoxyphenyl)chroman-4,6-diol. ¹H NMR (300 MHz, d₆-DMSO) δ: 8.75(s, 1H), 7.28 (t, 1H, J 15.7, 7.9 Hz), 6.96-6.99 (m, 2H), 6.87 (dd, 1H,J 7.9, 2.5 Hz), 6.63 (d, 1H, J 8.3 Hz), 6.52 (d, 1H, J 2.9 Hz), 6.48 (s,1H), 4.95 (dd, 1H, J 9.8, 2.2 Hz), 3.75 (s, 3H), 2.82-2.89 (m, 1H),2.57-2.66 (m, 1H), 2.06-2.13 (m, 1H), 1.89-1.97 (m, 1H).

d) 2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine

2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine was prepared asdescribed for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(3-methoxyphenyl)chroman-6-ol. ¹H NMR (400 MHz,d₆-DMSO) δ: 9.04 (d, 1H, J 2.9Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.32(t, 1H, J 15.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 8.4 Hz),7.01 (s, 1H), 7.00 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.92(d, 1H, J 8.7 Hz), 6.90 (dd, 1H, J 8.4, 2.6 Hz), 5.12 (dd, 1H, J 10.0,2.3 Hz), 3.77 (s, 3H), 2.93-2.97 (m, 1H), 2.71-2.77 (m, 1H), 2.15-2.20(m, 1H), 1.99-2.05 (m, 1H).

Example 100 6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine

6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine was prepared asdescribed for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26using 300 mg 2-[2-(3-methoxyphenyl)chroman-6-yloxy]-5-nitropyridine(Example 99(d)) and 1.0 g of Zn. H NMR (400 MHz, d₆-DMSO) δ: 7.51 (d,1H, J 3.0 Hz), 7.31 (t, 1H, J 15.8, 7.9 Hz), 7.04 (dd, 1H, J 8.7, 3.0Hz), 6.99-7.02 (m, 1H), 6.99 (d, 1H, J 2.6 Hz), 6.90 (dd, 1H, J 8.9, 2.6Hz), 6.79-6.81 (m, 1H), 6.72-6.74 (m, 2H), 6.69 (d, 1H, J 8.9 Hz), 5.06(dd, 1H, J 9.9, 2.2 Hz), 4.50 (s, 2H), 3.77 (s, 3H), 2.88-2.95 (m, 1H),2.66-2.71 (m, 1H), 2.12-2.17 (m, 1H), 1.94-2.00 (m, 1H).

Example 101N-{6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide

N-{6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide wasprepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27starting from 6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine(Example 100). ¹H NMR (400 MHz, d₆-DMSO) δ: 10.04 (s, 1H), 8.27 (d, 1H,J 2.7 Hz), 8.01 (dd, 1H, J 8.9, 2.7 Hz), 7.32 (t, 1H, J 15.7, 7.8 Hz),7.02 (d, 1H, J 8.8 Hz), 7.00 (d, 1H, J 2.5 Hz), 6.92 (d, 1H, J 8.9 Hz),6.90 (dd, 1H, J 8.2, 2.5 Hz), 6.84-6.86 (m, 3H), 5.09 (dd, 1H, J 9.9,2.1 Hz), 3.77 (s, 3H), 2.91-2.95 (m, 1H), 2.68-2.74 (m, 1H), 2.14-2.18(m, 1H), 2.04 (s, 3H), 1.97-2.02 (m, 1H).

Example 102 2-(3-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

2-(3-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was preparedas described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example1(b) starting from 2-(3-methoxyphenyl)chroman-4,6-diol (Example 99(b)).¹H NMR (400 MHz, d₆-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, 9.1,2.9 Hz), 7.34 (t, 1H, J 15.7, 7.8 Hz), 7.25 (d, 1H, J 2.4 Hz), 7.22 (d,1H, 9.1 Hz), 7.00-7.06 (m, 3H), 6.92 (dd, 1H, J 8.8, 2.4 Hz), 6.88 (d,1H, J 8.8 Hz), 5.64 (d, 1H, J 6.4 Hz), 5.27 (d, 1H, J 10.7 Hz),4.95-5.00 (m, 1H), 3.79 (s, 3H), 2.30-2.35 (m, 1H), 1.92-2.01 (m, 1H).

Example 103 6-(5-Aminopyridin-2-yloxy)-2-(3-methoxyphenyl)chroman-4-ol

6-(5-Aminopyridin-2-yloxy)2-(3-methoxyphenyl)chroman-4-ol was preparedas described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example26 using 138 mg2-(3-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 102)and 457 mg of Zn. ¹H NMR (400 MHz, d₆-DMSO) δ: 7.52 (d, 1H, J 3.0 Hz),7.32 (t, 1H, J 15.7, 7.8 Hz), 7.06 (dd, 1H, 8.7, 3.0 Hz), 7.01-7.04 (m,3H), 6.91 (dd, 1H, J 8.6, 2.4 Hz), 6.78-6.80 (m, 1H), 6.76 (d, 1H, J 8.7Hz), 6.71 (d, 1H, J 8.6 Hz), 5.54 (d, 1H, J 6.5 Hz), 5.19 (d, 1H, J 10.6Hz), 5.01 (s, 2H), 4.88-4.94 (m, 1H), 3.78 (s, 3H), 2.27-2.32 (m, 1H),1.87-1.96 (m, 1H).

Example 1046-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamineHydrochloride

6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamine wasprepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine inExample 26 starting from5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine(Example 84).6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamine wasisolated as its dihydrochloride salt. ¹H NMR (400 MHz, CDCl₃) δ: 8.20(d, 1H, J 2.1 Hz), 7.87 (dd, 1H, J 8.9, 2.1 Hz), 7.41-7.44 (m, 4H),7.37-7.40 (m, 1H), 6.98 (d, 1H, J 8.9 Hz), 6.97 (d, 1H, J 8.8 Hz), 6.93(d, 1H, J 2.7 Hz), 6.80 (dd, 1H, J 8.8, 2.7 Hz), 5.20 (dd, 1H, J 9.6,1.9 Hz), 3.30 (dd, 1H, 13.2, 9.6 Hz), 3.12 (dd, 1H, 13.2, 1.9 Hz).

Example 105N-[6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-yl]acetamide

N-[6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-yl]acetamidewas prepared as described for5-N′-acetylamino-2-(2-phenylchroman-6-yloxy)-pyridine in Example 27starting from6-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamine. ¹HNMR (400 MHz, CDCl₃) δ: 8.07-8.11 (m, 2H), 7.40-7.42 (m, 4H), 7.36-7.39(m, 1H), 7.15 (br s, 1H), 6.94 (d, 1H, J 8.8 Hz), 6.90 (d, 1H, J 2.8Hz), 6.88 (d, 1H, J 9.1 Hz), 6.78 (dd, 1H, J 8.8, 2.8 Hz), 5.17 (dd, 1H,J 9.6, 1.9 Hz), 3.28 (dd, 1H, 13.2, 9.6 Hz), 3.08 (dd, 1H, 13.2, 1.9Hz), 2.19 (s, 3H).

1. A compound of formula (I):

wherein X is —O; Z is —CHR₉—; Y is —CH₂—, —C(O)—, CH(OR₁₀)—,CH(NR₁₁R₁₂); R₁ is

R₂ and R₃ are independently H, lower alkyl, lower alkoxy, —NO₂, halogen,—CF₃, —OH, —NHR₈ or —COOH, R₆ is —NO₂, —NR₁₄R₁₉, —CF₃ or

R₈ is H, alkylcarbonyl, or alkenylcarbonyl, R₉ is H or lower alkyl, R₁₀is H, alkylsulfonyl, alkylcarbonyl, or alkenylcarbonyl; R₁₁ and R₁₂ areindependently H, lower alkyl, alkylcarbonyl, or alkenylcarbonyl, R₁₃ andR₁₈ are independently H or —OR₂₀, R₁₄ and R₁₉ are independently H,alkylcarbonyl, alkenylcarbonyl, alkylsulfonyl, C(S)NHR₁₇ or C(O)NHR₁₇,R₁₇ is H or lower alkyl, R₂₀ is H, alkylcarbonyl, or alkenylcarbonyl, ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein formula (I) has the structure of formula (Ib)


3. A compound according to claim 1, wherein X is O, and Z and Y are—CH₂—.
 4. A compound according to claim 1, wherein X is O, Z is —CH₂ andY is CHOH.
 5. A compound according to claim 1, wherein R₆ is NO₂ or—NR₁₄R₁₉.
 6. A compound according to claim 5, wherein R₁₄ and R₁₉ areindependently H, alkylcarbonyl, alkenylcarbonyl, or alkylsulfonyl.
 7. Acompound according to claim 1, wherein R₂ and R₃ are independently H orhalogen.
 8. A compound according to claim 7, wherein halogen isfluorine.
 9. A pharmaceutical composition comprising a compound of claim1 together with a pharmaceutically acceptable carrier.